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Easier Way to Convert Proteins into Crystals

ScuttleMonkey posted more than 7 years ago | from the crystal-clear-science dept.

Biotech 92

Roland Piquepaille writes "As you might know, proteins need to be transformed into 3-D crystals before their atomic structures and their properties can be analyzed. And production of high quality crystals from proteins has been a difficult task until now. But scientists in the U.K. have successfully used a porous medium, or 'nucleant,' a material that encourages protein molecules to crystallize. Their first step towards 'holy grail' of crystallography could help speed up the development of new medicines and treatments."

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This is Big (5, Informative)

eldavojohn (898314) | more than 7 years ago | (#14501492)

Ok, so I don't know a ton about nuclear medicine, I know just enough to be dangerous. Protein crystallization allows us to see it's structure [] whereby we better understand its function [] .

The reason this bit of news is so big is that it will (hopefully) allow researchers a way to quickly look at the structures of proteins in such as (in the second link) infectious diseases transmitted by prions, or protein particles. Prions seem to be pure protein; they contain neither DNA nor RNA.

If we can understand the shape and formation of proteins, we can understand how viruses and cells work because proteins are the building blocks. Viruses are obviously first on the chopping block as they are the smallest and infect millions of people world wide (AIDS, influenza, the common cold, etc.).

Re:This is Big (1)

poeidon1 (767457) | more than 7 years ago | (#14501537)

I always thought that DNA contains proteins , and not proteins contain DNA, ATGTTA....

Re:This is Big (0)

Anonymous Coward | more than 7 years ago | (#14501680)

No DNA contains nucleic acids. Proteins are made up from amino acids.

Re:This is Big (1)

Verde (40099) | more than 7 years ago | (#14501707)

DNA provides the roadmap for the construction of proteins. Each nucleic acid triplet translates into a particular amino acid along the chain.

Re:This is Big (0)

Anonymous Coward | more than 7 years ago | (#14502759)

You always thought wrong.

Also, you have poor reading comrehension. The poster didn't say that PROTEINS don't contain DNA; he said that PRIONS don't contain DNA.

DNA vs. Chromosomes (1)

kramtark (767724) | more than 8 years ago | (#14510914)

I think you are thinking of chromosomes, which owe their structure to proteins.

Re:This is Big (0)

antifoidulus (807088) | more than 7 years ago | (#14501545)

Yes, but attacking prions will allow us to eat raw cannibalistic cow brain with impunity!

Re:This is Big (0)

Anonymous Coward | more than 7 years ago | (#14501656)

I usually eat it with fries and a chocolate shake. mmm, happy meal!

Re:This is Big (1)

Orrin Bloquy (898571) | more than 7 years ago | (#14501558)

Also, by converting proteins to crystals, it enables us to arrange them into superstructures which can be rapidly oxidized in a fused silicate tube and subsequently internally analyzed by lung tissue.

Re:This is Big (1)

eldavojohn (898314) | more than 7 years ago | (#14501606)

Also, by converting proteins to crystals, it enables us to arrange them into superstructures which can be rapidly oxidized in a fused silicate tube and subsequently internally analyzed by lung tissue.
My god, with this technology, we could manufacture the purest Methamphetamine known to man.

Party at Imperial College London tonight! Thank meth Doctor Stephenson!

Re:This is Big (5, Informative)

ruckerz2k (653900) | more than 7 years ago | (#14501706)

Though the parent is correct, this technology greatly reduces the time and effort involved in 'crystallizing' proteins. Most common approach is to use the hanging drop method [] , where a drop of the sample is suspended over a highly concentrated solution. The sample concentrates due to the negative osmotic pressure and the protein 'crystallizes'. The crystallization process can be hastened by using a 'nucleant', usually a small crystal of the sample that you have previously crystallized. Also, the exact identity and composition of the concentrated solution is varied in order to find the right crystallization conditions. This is a very tedious process (imagine setting up 96 different concentrated solutions, each differing in about 1% concentration of the solutes) and time intensive.

The discovery of a 'universal' nucleant (close to the one suggested by the authors of this study) and the development of a matrix to encourage crystallization would greatly speed the screening process, and ultimately, crystallization of proteins.

More importantly... (2, Insightful)

cryptochrome (303529) | more than 7 years ago | (#14501708)

By speeding up the (currently extremely tedious) process of crystallization and hopefully making inroads into the ~70% of all protein which currently can't be crystallized, this will rapidly improve our understanding of the structures of whole classes of proteins.

Re:This is Big (1)

Verde (40099) | more than 7 years ago | (#14501798)

Getting a protein in solution to precipitate as a well-formed crystal is the first step in using X-ray crystallography to determine its structure. This first step, at least until now, has been more art and magic than science. This breakthrough doesn't do anything to speed up the structure determination, which will still take a long time for each protein being studied.

Re:This is Big (3, Informative)

SIGFPE (97527) | more than 7 years ago | (#14501827)

Talk about Karma whoring! A bunch of sentences culled from a variety of sources from someone who really doesn't know what they are talking about. Now that's dangerous.

Viruses are obviously first on the chopping block...

Non "obviously" at all. There are countless medical applications for X-ray crystallography. Any time you want to study the structure of a protein it comes in handy. Many diseases are attacked by researchers from the point of view of receptor binding - the binding together of proteins to other compounds like a lock and key. Such receptors act like switches activating or controlling biological processes. These are ubiquitous in nature and understanding the shape of these 'locks' and 'keys' can be useful in trying to understand the mechanisms of all kinds of diseases whether or not they are caused by pathogens.

Re:This is Not so Big (5, Informative)

sam_handelman (519767) | more than 7 years ago | (#14501837)

This is an improvement on a known technique. The abstract [] is as over-reaching as the press release (the linked article).

  I'm not a crystallographer, but I work in a lab group that has many crystalographers in it.

  It's been known for some time that you can use a variety of materials - including things with porous surfaces, which is what is used here - to assist the process of crystallization. Crystalization is difficult and, frankly, rather unscientific - you take the protein you want to crystallize, and you try different techniques and tricks (of which porous nucleants are an example) until you can get it to work.

  So, okay, it would be a "holy grail" if you could find one technique that would let you crystallize most things without going through all that trouble.

  However, based on only seven examples (Subscribers only, I'm afraid. [] ), you absolutely cannot conclude that this is a universal nucleant - based on the similarity among the seven examples, I'd be very surprised if it were; even if it were a universal nucleant, nucleation does not always guarantee usable crystals.

  Those caveats aside, it does look like a useful advance.

Re:This is Not so Big (2, Interesting)

poincaraux (114797) | more than 7 years ago | (#14504227)

Crystalization is difficult and, frankly, rather unscientific
You're not kidding. My favorite example is the fact that many crystallographers add diet coke to aid in crystallization.

Re:This is Big (2, Interesting)

DerCed (155038) | more than 7 years ago | (#14501846)

Yeah, you've got it mostly right.
In structural biology, the x-ray crystallographers try to find out the exact 3-dimensional structure of a single protein. Since almost everything in the biochemistry of the human body works with proteins, they are a common target for drugs!

The problem in crystallization lies in the properties of the proteins themselves. They are flexible, dynamic, fragile little machines which SHOULD NOT crystallize in your cells (exactly this happens in diseases linked to prions). So they are very soluble in water. Researchers try to find the right conditions (salts, precipitants, etc.) to get them to build little crystals. Often, this process takes months or years.

This new technique will hopefully fasten it up!

Re:This is Big but not that big (2, Interesting)

Asam (946934) | more than 7 years ago | (#14502002)

Sure being able to find suitable crystallization conditions for proteins is a bottleneck at the moment and this will aid in the process and add to the 20,000 plus know Protein structures, however, this is limited to certain types of proteins. A lot of really interesting proteins however are more flexible, and its this flexibility thats the key to understanding a lot of protein function. Structures derived from crystals don't give so much information about protein dynamics and molten globule like states of proteins, in fact when you crystallize proteins they tend to be locked into one conformation. Everyone in the field should keep this in mind always. A protein structure derived from a crystal structure is just a framework, its not a final representation of final function. More clues about this kind of information can be derived from NMR (Nuclear Magnetic Resonance), however the use of NMR is restricted to relatively small proteins. This is going to help, but its not huge, the real breakthrough will come when we can model any given protein sequence on a computer and have an acurate predicated 3 diminsional structure together with it molecular motions and dynamics in real time. Glad to see /. covering the field, its huge and its just started, we're at the begining of an exponential curve. Maybe /. should make a seperate section for this, I'd certainly be interested in contributing articles and news to such an effort.

Re:This is Big (1)

Elwood P Dowd (16933) | more than 7 years ago | (#14502045)

Prion disease kills less people than lightning.

It's important to fix for a number of reasons, but way less important than the many other areas of medicine in which this development could be useful.

In my even less informed opinion.

I don't know a ton about nuclear medicine. (2, Informative)

Anon.Pedant (892943) | more than 7 years ago | (#14502558)

Quibble #1: This is not "nuclear medicine", it is "structural biochemistry."
The field of nuclear medicine is concerned with things like radiation therapy and PET scanning.

 htm []

Quibble #2: Your second link is very outdated. Structures for several prion proteins were determined several years ago, using both X-ray diffraction and NMR methods. Science moves on, but many webpages are never updated.

How hard can it be? (2, Funny)

AtomicBomb (173897) | more than 7 years ago | (#14502687)

I observe this phenomenon all the time on top of my uncleaned plates in the kitchen sink :)

Re:This is Big (not as big as your Karma Whoring!) (0)

Anonymous Coward | more than 7 years ago | (#14503009)

Eldavojohn = World Class Karma Whore (TM)

No, actually... (-1, Troll)

Nom du Keyboard (633989) | more than 7 years ago | (#14501522)

As you might know, proteins need to be transformed into 3-D crystals before their atomic structures and their properties can be analyzed.

No, I never knew that.

But I do now.

An Even Easier Way to Convert Proteins to Crystals (1, Insightful)

digitaldc (879047) | more than 7 years ago | (#14501527)

Drink lots of beer and then pee in the snow.

Re:An Even Easier Way to Convert Proteins to Cryst (2, Informative)

napalmfires (946900) | more than 7 years ago | (#14501614) [] Urine doesn't have protein in it...

Re:An Even Easier Way to Convert Proteins to Cryst (1)

painQuin (626852) | more than 7 years ago | (#14501666)

does beer? I think that's what was meant.. beer -> snow

Re:An Even Easier Way to Convert Proteins to Cryst (0)

Anonymous Coward | more than 7 years ago | (#14501815)

Unless the urinator has kidney damage!

Re:An Even Easier Way to Convert Proteins to Cryst (1)

Austerity Empowers (669817) | more than 7 years ago | (#14501830)

Urine SHOULDN'T have protein in it.

Re:An Even Easier Way to Convert Proteins to Cryst (1)

sam_handelman (519767) | more than 7 years ago | (#14501869)

It does if you are sufficiently sick. [] (link pulled off of google but it makes the point.)

  That said, even if you do have peptides in your urine, they don't crystallize when it hits the snow.


Re:An Even Easier Way to Convert Proteins to Cryst (1)

AlfredoLambda (654892) | more than 7 years ago | (#14502330)

Normal urine has proteins indeed: []

"Hyaline Casts

These casts are the most common type of cast, and often they can be found in normal urine samples, especially after vigorous exercise. Hyaline casts result from the solidification of Tamm-Horsfall protein, which is secreted by renal tubular cells and may be seen without significant or abnormal proteinuria."

Re:Slashdot Moderation At Its Best (0, Offtopic)

j37hr0 (904581) | more than 7 years ago | (#14501887)

Why is this Smart Ass comment, modded up 3 as Insightful? WhiskeyTangoFoxtrot? Maybe modded to 2 as funny. MAYBE.

Re:An Even Easier Way to Convert Proteins to Cryst (1)

StupidStan (773027) | more than 7 years ago | (#14502812)

since beer doesnt have protein (enough to mention if it does) a more appropriate method would be to eat a high-protein mexican diet, then go visit the snow... it would be about the same constistancy

Re:An Even Easier Way to Convert Proteins to Cryst (2, Funny)

Mignon (34109) | more than 7 years ago | (#14503369)

Or, if you want to convert crystals to protein, buy a girl some diamonds and see what she does to thank you...


Anonymous Coward | more than 7 years ago | (#14503451)


Oblg. FQ Quote (1)

Corbu Mulak (931063) | more than 7 years ago | (#14503784)

Dimonds...she'll pretty much have to

Obligatory Python (-1, Offtopic)

Anonymous Coward | more than 7 years ago | (#14501544)

Will this quest for the Holy Grail end up with everyone getting arrested?

...if it wasn't for those darn kids!! (1)

Control Group (105494) | more than 7 years ago | (#14501566)


They've beaten me to the protein-to-crystal technology that was to be the core of my patent-pending Doomsday Device!

I wonder what the DeathLegion's union rep will say when I announce 10,000 layoffs...

sigh (-1, Flamebait)

jcgeuze (943829) | more than 7 years ago | (#14501589)

so lets quickly patent it, and make it so expensive that 95% of the world who really needs it can't afford it.

I crystalize my proteins... (0, Funny)

Anonymous Coward | more than 7 years ago | (#14501611)

...using Kleenex for the nucleation process.

Roland (-1, Troll)

Anonymous Coward | more than 7 years ago | (#14501620)

Roland, if you rub my cawk long enough, I'll spout out some protein and you can turn it into crystals for me by letting it dry and cake on your lips.

W00t! (0, Offtopic)

SharpFang (651121) | more than 7 years ago | (#14501624)

Roland Piquepaille's article not linked to his blog outside of the "credit link"? I wonder, did Roland make a mistake or maybe Scuttlemonkey read my post [] ?

Re:W00t! (2, Informative)

Red Flayer (890720) | more than 7 years ago | (#14501807)

Did you check the submitter link? rel=nofollow. Maybe if you'd read the commments by Taco in last weeks /.metaarticle, you'd see why.

Twenty Seconds Into The Future (0)

Anonymous Coward | more than 7 years ago | (#14501743)

-------------------- CUT HERE --------------------

Everything above this line are lame jokes from people who couldn't be bothered to read the article.

Thirty Seconds Into The Future (0)

Anonymous Coward | more than 7 years ago | (#14501756)

I thought the jokes were kind of funny

Re:Thirty Seconds Into The Future (1)

painQuin (626852) | more than 7 years ago | (#14501776)


Ever hear of NMR structure determination? (1)

acidfast7 (551610) | more than 7 years ago | (#14501767)

Roland Piquepaille writes "As you might know, proteins need to be transformed into 3-D crystals before their atomic structures and their properties can be analyzed.
Ever hear of using NMR to determine tertiary structure in solution? Just for the record, it doesn't require cystals.

Re:Ever hear of NMR structure determination? (3, Informative)

Red Flayer (890720) | more than 7 years ago | (#14501848)

NMR diesn't rquire crystallization, but it does require transfer of the protein to a non-native solution (which may affect tert structure). Not that crystallization doesn't do this also...

Plus, NMR results or more vague than X-Ray crystallography, and can only be used with small proteins, whereas crystallography works for even very large proteins (provided you can get them crystallized).

Re:Ever hear of NMR structure determination? (1)

acidfast7 (551610) | more than 7 years ago | (#14502291)

I understand what you're saying.

I just don't like the use of absolutes by the person who submitted the article.

Both tehcniques have pros and cons and the best approach (given infinite time and money) would be to employ both in parallel. In fact, I believe that with the adavnces in NMR technology, it will one day replace the use of X-ray crystallography.

Also a scientist, you'd even be more marketable with both skillsets at the end :)

Re:Ever hear of NMR structure determination? (1)

Red Flayer (890720) | more than 7 years ago | (#14502761)

I thnk you're right on all counts, except maybe your last point (generalization may preclude being 'tops' in either method).

I suspect that the submitter:
(1) Isn't up on the subject, and
(2) Didn't bother to do some background research before submitting.

Still, I'm glad the article was submitted and posted :)

Re:Ever hear of NMR structure determination? (2, Informative)

Bowling Moses (591924) | more than 7 years ago | (#14502553)

The molecular weight limit of NMR has been increasing quite a bit and now proteins on the order of 100 kDa are possible, although technically challenging. Lewis Kay's group at the University of Toronto has done a solution structure of an 80 kDa protein, for instance.

Re:Ever hear of NMR structure determination? (1)

Red Flayer (890720) | more than 7 years ago | (#14502721)

Wow. Considering that the practical limit 5 years ago was around 35 kDa IIRC, that's impressive.

Re:Ever hear of NMR structure determination? (1)

jclin (805874) | more than 7 years ago | (#14503459)

I take exception to the "NMR results [are] more vague than X-Ray crystallography". If you do NMR structure determination, you would know that it doesn't have to be that way. It depends on how much information you can get from the NMR NOESY spectra, which is basically a map that tells you which hydrogen atoms are close to other hydrogen atoms. The "vague" statement may refer to the simulations that are required to transform the NMR spectrum into a structure. However, X-ray crystallography also requires computer manipulation in order to interpret the diffraction pattern into a structure. If the pattern is not well defined, one gets a structure with large errors. This, in my opinion, could be called "vague".

In fact, there is extra information that may be discerned from NMR that x-ray cannot easily determine: fluxionality. A well-known, but somewhat new theory, describes the "breathability" of proteins and its importance in protein function. Good crystals, by definition, may mistakenly label a fluxional part of the protein as well-defined and not moving. NMR structure determination, however, does not make those mistakes. Why does this matter? In some proteins, the moving parts are central to answering how the protein functions.

It's also my feeling that non-native solution is more pertinent to nature than a crystalline solid, so it's a mistake to equate the two shortcomings. The only thing that x-ray has going for it is it's ability to easily determine the structure of large proteins. However, as magnets get larger, and the technology gets better (including hydrogen-assignment computer algorithms?), magnet jockeys may close the size gap on crystallographers.

Re:Ever hear of NMR structure determination? (1)

capt_mollusk (947087) | more than 8 years ago | (#14506560)

Not sure what you mean by "non-native" solution. The protein will (hopefully) be in a native conformation in the buffer. But NMR does suffer from size limitations and is only possible for rather small proteins, at the moment. Advances in pulse sequences may improve the performance. (Nuclear magnetic resonance relies on radio pulses in a very strong magnetic field (>10 Tesla) to observe "relaxation" in the aligned molecules. It is the same as MRI, but no one wants a medical procedure with "Nuclear" in the title.)

Also, the solution to NMR data may have quite a bit more error in it than crystallography. NMR is not a "global" fit, but rather a mathematic solution relating the positions of each atom to its nearest neighbor, so which each nearest neighbor you can propagate a small error that can get large across the whole structure. This is usually more of a problem for nucleic acids than proteins, and the use of dipolar couplings can improve the global fit of the model.

At this point, x-ray crystallography is more for analyzing complexes, which tend to be larger, and NMR more for fragments, but they each have their niche.

as a final note, just because NMR does not rely on crystals does not mean it is easy. It is very difficult to find a buffer condition that keeps the protein at extremely high concentration yet does not precipitate, etc. And that does not even get into the problems surrounding collecting clean data.

Re:Ever hear of NMR structure determination? (1)

pan_sapiens (647704) | more than 8 years ago | (#14508388)

Plus, NMR results or more vague than X-Ray crystallography, and can only be used with small proteins,

This is a common misconception, and while Xray structures are often more *precise*, they are not always more *accurate*. It is also somewhat like comparing apples and oranges, since one is in a crystal, the other is more free to move without distortion in solution

Protein structures determined by NMR are typically represented as an ensemble of possible 'best fits' to the observed NMR data, and so often they appear more 'vague' or 'fuzzy'. The pictures which are usually published show a number (~20) of the best structures all overlayed, and it can look a bit like a bundle of strands compared to an Xray structure, which are represented as the 'one true structure'.

The truth is, that Xray structures are also simply a best fit to the observed data, which can be good in some places, and very poor and fuzzy in others. This goodness of fit is usually stored as the B-factor (or "temperature factor") along side the atomic coordinates, but the average non-structural biologist doesn't look at the B-factor, and just assumes that the Xray structure is reliable. The upshot is that some Xray structures appear much more *precise* in parts than they really are (and that's not even getting into the relevance of structures in a crystal vs. in a solution closer to their native environment).

It turns out that for proteins with both NMR and Xray structures available, generally (but not always) the regions which are fuzziest in an NMR structure correspond to the same regions with high B-factors in the Xray structure.

The one thing that Xray structures really don't tell us about is often the most important property when it comes to protein function ... the dynamics .. the motion. NMR structures often reflect this mobility in the precision of the coordinates, and by analysis of NMR relaxtion data it can be verified that much of the time the fuzziness in the structure is not simply due to lack of structural data in this region of the protein, but also due to dynamic motion.

On a related note .. it is possible to measure residual dipolar couplings by NMR at a precision such that certain bond vectors are more precisely defined than the equivalent vectors in most Xray structures (Ad Bax did this ... can't find the reference right now). While this technique is not in common enough usage to be producing super-precise NMR structures every day, it is helping close the gap considerably for those who are applying it. That said, the smart approach is to use Xray and NMR in parallel. A few years ago I saw a talk summarising the findings of a prominent North American Structual Genomics program. In the first few years, they had basically solved the same amount of protein structures by NMR as they had by Xray. It goes to show that structure quality comparisons aside, both methods have their own strengths, and those that restrict themselves to only one of these techniques effectively halves their chances of producing a protein structure.

(I am a structural biologist by trade ... probably explains the semi-rant on this topic. I could go on - encouragement accepted with gusto)

Re:Ever hear of NMR structure determination? (2, Interesting)

PDoc (841773) | more than 7 years ago | (#14502148)

NMR is great, because it's fast, relatively easy to run, and tolerant of substrate. But it isn't absolutely accurate. Techniques such as nOesy and cosey allow for determination of stereochemistry via two-dimensionaly NMR, showing contact through bonding and through-space interactions. However the data from a nOe experiment can be inconclusive, especially in cyclic systems. Only X-ray data can actually confirm the true structure then.
A friend, also doing a Ph. D in chemistry, has just binned half his thesis because the NMR data lead to one conclusion, only to be contradicted by the X-ray data. And this wasn't a small difference either...
Oh well, back to the lab then...

Re:Ever hear of NMR structure determination? (1)

recycledpork (808313) | more than 7 years ago | (#14504299)

NMR has an inherit weight limit. Relatively few protein structures are found using it, most are done by XRAY-C. Currently, of all proteins structured, 5000 are by NMR 28,000 by XRAY. See tion/pdb_statistics/index.html&tb=false []

Understanding protein structure.. (2, Informative)

jonasmit (560153) | more than 7 years ago | (#14501785)

is critical to translating the information obtained in, for example, the Human Genome Project. The DNA gives us the blueprint but the protein does the work. Currently, there is no way to predict protein structure from DNA. Therefore, you must see the structure to understand how the protein works. Also it is important to note that in Protein-Protein interactions. Protein-Protein interactions are important in normal cell singalling events as well as in how virii infect cells (like HIV1 binding to gp120/gp41).

Re:Understanding protein structure.. (1)

Miraba (846588) | more than 7 years ago | (#14502686)

You appear to be missing something.

Also it is important to note that in Protein-Protein interactions.

Note what in protein-protein interactions? I have no idea what you're talking about, unless you're being redundant in regards to the preceding or following sentences.

Re:Understanding protein structure.. (1)

jonasmit (560153) | more than 7 years ago | (#14502848)

You are right I can't type today..disregard that sentence

Re:Understanding protein structure.. (2, Interesting)

Asam (946934) | more than 7 years ago | (#14502709)

There are ways to obtain structure of proteins from DNA, just that they're not so good if a similar structure doesn't exist in the Protein Data Bank ( [] already, its called homology modelling. You have the protein sequence of an unknown structure then look for similiar sequences in the 20,000 known protein structures. That's why the more structures we add to the PDB makes it easier to find structures of unknown proteins.

Re:Understanding protein structure.. (0)

Anonymous Coward | more than 7 years ago | (#14502849)

Apparently, medical companies are in a rush to find protein structures that may lead to medical developments and patent them wildly.
The Welcome Trust funds several projects [] around [] the world [] that try and find as many structures before they are patented, and release them to public domain.
The way they do it is by massive trial and error. They test many environments for crystallization in parallel using robots and some neat tech.

Re:Understanding protein structure.. (1)

jclin (805874) | more than 7 years ago | (#14503709)

The computer programs [] that predict protein structure from its primary structure are getting better. So there is a way.... []

Nobel Prize material (4, Funny)

smellsofbikes (890263) | more than 7 years ago | (#14501786)

To find the three-d structure by x-ray crystallography, you have to crystallize the protein. Actually doing so, with different proteins, is an astoundingly difficult task, so much so that something like five Nobel prizes have been given for research into crystallization and x-ray crystallography development, and another ten or so Nobels given for determination of three-d structure of various proteins were, in essence, awarded for getting the protein to crystallize.

Side story: there was a famous German chemist named Emil Fischer, who originally determined the structures of a bunch of sugars. That was, again, largely a crystallization problem. He had, as Germans did in the 1890's, an enormous beard, and was playing with chemicals all day long, which tended to condense in his beard. It was said that if you could not get something to crystallize out of solution, no matter what you did, you asked Fischer to come to your lab and fluff his beard over your beaker, and the seed crystals falling from it were of such variety that one was almost guaranteed to be correct for your particular situation and get it to crystallize. So this isn't exactly NEW technology.

This should impact future graduate students (4, Insightful)

radiashun (220050) | more than 7 years ago | (#14501788)

Hopefully this will encourage more individuals to pursue advanced degrees in protein crystallography. I was recently at a talk where a soon-to-be PhD was discussing her crystallography work. She said that many people choose to pursue other areas in biochemistry/structural biology because protein crystallography is very unpredictable. Some proteins will crystallize in months while others can take YEARS! Waiting years before you can really dive into your PhD research is very discouraging.

Re:This should impact future graduate students (1)

sdpuppy (898535) | more than 7 years ago | (#14502625)

It is also a fairly lucrative field, and you need people with advanced degrees.

Did you ever see the prices that a crystallographic lab charges (even for academia)?

I don't think that NMR people get paid as well...

Re:This should impact future graduate students (1)

staticx0085 (794487) | more than 8 years ago | (#14505647)

It is true that we need more people in the field, but we need people to improve on current techniques, such as the researchers mentioned in the article. We don't just need more people using the same old methods. Currently protein crystallization is almost all trial and error, which obviously isn't most efficient way to do much of anything. I currently work in a crystallography lab myself, and I can tell you from expereince that it is an extremely painful process. While the human genome project was a huge advancement, we still need to know what all of those genes look like as proteins, and we're not even remotely close to solving all the structures.

P.S. for everyone who says that NMR is "better" clearly doesn't know much about the field. While it is useful, it only works on small proteins of fragments of proteins and doesn't give anywhere near the same detail as good x-ray diffraction data.

it least (0, Offtopic)

minus_273 (174041) | more than 7 years ago | (#14501789)

well, at least it isnt Beatles-Beatles.

Roland Piquepaille knows nothing. (1, Informative)

Anonymous Coward | more than 7 years ago | (#14501811)

Roland Piquepaille writes "As you might know, proteins need to be transformed into 3-D crystals before their atomic structures and their properties can be analyzed.

Simply NOT TRUE.

Proteins must be crystalized before they can be analyzed by X-ray crystallography. They can be analyzed by many, many other methods even if they aren't crystals. And frankly, given that proteins aren't in crystalline form in the body, knowing the crystalline form isn't always useful.

NMR (nuclear magnetic resonance) spectroscopy will elucidate the stucture of a protein in solution, which is normally far more useful.

Aside from chemists, biologists & MDs, most people (including paparazzi like Roland)haven't heard of NMR.

Re:Roland Piquepaille knows nothing. (1)

drooling-dog (189103) | more than 7 years ago | (#14502011)

For high-resolution structures of large molecules, X-Ray crystallography is still the way to go.

Re:Roland Piquepaille knows nothing. (2, Interesting)

cruachan (113813) | more than 7 years ago | (#14502220)

I'm afraid not. Nothing beats having an accurate structure from Px. I spent several years as a postdoc attempting to grow large crystals of a membrane protein (at the time one of the first three or four membrane proteins to be crystallized). As we really were interested in knowing the structure rather than how we got it as light relief from purifying the protein on a near industrial scale and seeding thousands of crystallization trials we tried every other structural analysis method we could get our hands on. Many of these gave us interesting and invaluable info, but in all cases they were of most interest after the crystal structure was solved and the results could be interpreted in the light of that.

With most Protein Chemistry having the Px structure is the Gold Standard, and you can't really say you understand a protein until you have it. Trouble is, that as the article says, getting crystals is hard, slow, and extrodinarily painstaking work

Re:Roland Piquepaille knows nothing. (1)

capt_mollusk (947087) | more than 8 years ago | (#14506642)

Indeed, there are techniques on the horizon to study atomic resolution without crystals, and the ability to observe a single molecule may be someday routine. But for atomic resolution (~1 angstrom or so) at ths time, nothing beats Roentgen's x-ray, equations of Laue and the Bragg, Bernal and Crowfoot's crystallization techniques, and an obscenely powerful digital computer (even though proteins were crystallized in 1918, the first structure coincides with digital computers 40 years later, as 3-D fourier transforms on this scale are not feasible using any other method).

NMR is not really "more useful", and certainly not because it is "in solution". The distortions of the NMR model are likely to be greater than those from the crysallographic model. A lot of work has gone into studying the caveats of each technique, and it is not meant to be a pissing contest. They are both tools, and each has a job. But people (including biochemists) hold the misconception that NMR is easier than crystallography, and more accurate. neither is remotely close to true.

Of course (0, Offtopic)

Tumbleweed (3706) | more than 7 years ago | (#14501824)

As you might know, proteins need to be transformed into 3-D crystals before their atomic structures and their properties can be analyzed.

I knew that.

Or don't crystallize at all(!) (2, Interesting)

infolib (618234) | more than 7 years ago | (#14502015)

It might be possible to determine protein structure with just a single molecule, no need for crystallization at all, e.g. with free electron lasers []

The brilliance of x-ray sources are right now undergoing a revolution much faster than Moore's law.

crystallization is tough stuff (2, Interesting)

!splut (512711) | more than 7 years ago | (#14502249)

IAASB (structural biologist), and while I can't verify their findings, I can back up the premise in the article that generating diffraction-quality protein crystals is one of the two major bottlenecks to X-ray crystallography (the other being purification).

It's pretty easy to understand why. Not only do you need pure protein, but one must find conditions under which that protein forms relatively large, single crystals. The chief variables, aside from the homogeneity of the protein you're starting off with, include temperature, pH, protein concentration, choice of and concentration of precipitant (generally a chemical that drives the protein out of solution), choice of and concentration of additive compounds, in some cases detergents... The researcher must traverse this multidemensional search space by trial and error, with a limited quantity of protein, looking for the optimal conditions. On top of that, the conditions that confer the ideal level of nucleation may not be ideal for crystal growth...

We have developed shortcuts over the past 20 years, or so. Kits are available that allow one to screen through frequently successful crystallization conditions. The number of conditions one can test in one go is gradually increasing, as things miniturize somewhat.

The ease-of-crystallization varies amazingly from one protein to another, and tricks that improve one do not necessarily work for another, but anything that simplifies the process will be greatly appreciated by the field.

Re:crystallization is tough stuff (3, Interesting)

BabyStewy (946954) | more than 7 years ago | (#14503296)

While I agree that this is a major advance, I think calling this the "holy grail" is going too far. Currently there a several ways of doing large screens for crystallization conditions which utilize robots and nanoliter volumes of protein/condition to screen thousands of precipitant mixtures. The two real major stumbling blocks in crystallography are purification of monodisperse, nearly homogeneous protein (with respect to post-translational modifications as well as identity of the protein species) and the real "holy grail" problem, which is ab initio phase determination.
Since X-rays cannot be lensed, the Fourier transform of the diffraction pattern (which is the Fourier synthesis of the ordered electrons in the crystal) requires knowing not only the intensities, a trivial task, but also the relative phase angle of each reflection. This is a problem with possible solutions on the order of 6^n, where n is the total number of unique reflections, or about 5-10,000 for an average macromolecular structure at 3 angstrom Bragg spacing, allowing for a +/- accuracy of 30 degrees for each phase angle. Current solutions rely on searching reciprocal space with similar known structures (Molecular Replacement) or several ab initio methods that require one or more heavy element derivatives of native crystals. The first approach only works for crystals where a very similar structure is already known and available to the investigator. The second approach requires further screening for heavy metals that bind in ordered sites in the crystal without significant alteration of the native lattice, then usually a trip to a tunable X-ray source at a synchrotron. This second approach can burn through an astounding number of crystals and investigator time. There are shortcuts such as making the protein with Seleno-methionine instead of methionine (selenium has a usable X-ray edge for phasing, unlike sulfur),but this is normally done after initial purification and crystallization have been optimized. For more reading on the phase problem, I'd recommend either Alexander McPherson or Jan Drenth's excellent introductory textbooks on macromolecular crystallography.

hmm, so now I can choose (1)

way2trivial (601132) | more than 7 years ago | (#14502732)

between burial, cremation, or crystilization?


As an x-ray crystallographer.. (0)

Anonymous Coward | more than 7 years ago | (#14502822)

I hope this comes to market soon, because determining the crystallization conditions of a new protein, protein - protein complexes or, protein - nucleic acid complexes is the most difficult part of structure determination. However, there are many protein - protein complexes that don't form regular complexes, that is the same proteins can bind to different parts of its binding partner protein. I wonder if their new material works with such proteins. Ohh and here's the link to the full article made available by for those who don't have PNAS subscriptions from their uni's:

Experiment and theory for heterogeneous nucleation of protein crystals in a porous medium []

Elric Bros.: "Been there, Done That" (1)

Bushido Hacks (788211) | more than 7 years ago | (#14502841)

In a related story, the university has built a town for residents to move into and a modest price.

Yep. Three and four bedroom homes that do not have transmutation circles covered up with wallpaper. Oh, and pay no attention to the symmetry of the town map or the position of the homes and businesses being positioned where they are. It's not a giant alchemy transmutation circle! You're silly and watch too much anime! It's a Rorschach test. Yeah! And from what I see I see two philosopher sto--stoner podering the meaning of life. Yep! Wo said anything about philosopher stones?! There you go again making stuff up. There's no such thing as homounculus, alchemy, or strange men with scars on their face with an arm transplant. Talk your happy pills and go back to sleep! And if you see a red glow duck and cover!

/Duck and cover doesn't work!

Re:Elric Bros.: "Been there, Done That" (0)

Anonymous Coward | more than 8 years ago | (#14505587)

This is one of those jokes that has a very large divide in humor value between those who "get it" and those who don't. Note to mods: this isn't quite Offtopic, but it may be LOL Spoilerzz!1.

Probably gonna start a flamewar, but... (2, Interesting)

cr0sh (43134) | more than 7 years ago | (#14503381)

If proteins can be crystalized (albeit with some difficulty), in order to study structure and makeup, then is the reverse true? That is, could some proteins be created from a crystal matrix?

I know this isn't a new idea. I don't have references handy to prove it isn't, I just know that I have read arguments about it. This theory is used to explain the origins of life (distinct from the theory of evolution). Basically, you have the whole "early earth molecular soup mix with electrical activity providing the spark-o-life" (Miller-Urey Experiment [] ), forming organic compounds, which are then (in some manner) "processed" by crystal structures forming later (?).

It makes me wonder if it wouldn't be possible to study crystals in a similar manner to see whether they could (in some manner) aid the formation of the organic compounds formed by the Miller-Urey (and other similar) experiments into early proteins or protein-like structures? Does anyone know if such a study has already been undertaken? Or, is this idea nothing more than baseless speculation with no foundation in reality? I am sincerely curious...

Re:Probably gonna start a flamewar, but... (1, Interesting)

Anonymous Coward | more than 7 years ago | (#14504075)

There are theories of the origins of life that invoke highly ordered matricies like montmorillonite clays that have been shown to catalyze some biologically relevant reactions, as well as induce the formation of lipid bilayer micelles, which would have been important for the formation of primordial cells. But for the most part, biologists agree that RNA probably came along before proteins, so looking for a template that could create RNA would probably be a better target.

But whatever the method, the way to make proteins would almost certainly not occur on a naturally formed crystal of another protein. Protein crystals don't form easily, and it's doubtful that they'd ever get concentrated and pure enough in the wild to crystallize on their own.

Sounds Like A Lot Of People Here Are Really Smart (1)

Doomedsnowball (921841) | more than 7 years ago | (#14503866)

Wow, structure, function... everyone has posted good comments. But isn't the real problem understanding how proteins FOLD! We know the make-up of many proteins, but do not understand HOW they work because it is tied up in exactly how they fold. This new method does not address this issue. Scientist are trying to understand how proteins work based on their shape AFTER they have folded. If we could figure out HOW they fold, we wouldn't have to examine each one individually. We could predict the final shape and function based on the knowledge of we have of the protein making intstructions and HOW THEY FOLD. Please people, assume everyone is an idiot before you go debate meaningless crap like how flat the earth is.

Re:Sounds Like A Lot Of People Here Are Really Sma (1)

DRAGONWEEZEL (125809) | more than 7 years ago | (#14504251)

Thats why I am a member of Team 11108 for FAH!

When I build a machine for a client, I try to encourage them to run the FAH core whenever their computer is on, and install it by default.

Re:Sounds Like A Lot Of People Here Are Really Sma (1)

jonissan (782693) | more than 7 years ago | (#14504373)

"If we could figure out HOW they fold, we wouldn't have to examine each one individually. We could predict the final shape and function based on the knowledge of we have of the protein making intstructions and HOW THEY FOLD." On the right track but knowing the shape a protein will fold to is not enough. We still need to know the structure-function relationship. Knowing how it will fold is a little closer, but it's not the holy grail either. The holy grail is knowing directly from the sequence what the function will be. Then we can make whatever you want. To the best of my limited knowledge knowing the shape a protein will fold into from its sequence is only part way. You still need to know what the function is of that structure you predicted. Unless you have some magical formula that relates structure to function you still need a library of similar structure-function relationships to predict the function of a particular protein and how that might change through further modification. That last part (modification) is the key IMHO.

Re:Sounds Like A Lot Of People Here Are Really Sma (1)

Doomedsnowball (921841) | more than 8 years ago | (#14507307)

How they fold is necessary knowledge to modify a protein. You don't need to know a modified protein's ultimate function BEFORE you make and test it. The testing would tell you that. But the structure IS the function when it comes to proteins, based on how they work. By coupling with complementary receptors, the proteins express themselves many different ways. This is thought to happen with some proteins in the middle of completely folding, thus expressing two separate functions.

Re:Sounds Like A Lot Of People Here Are Really Sma (2, Informative)

SyvanX (943054) | more than 7 years ago | (#14504404)

I've thought about this plenty, but to have some benchmarks for the shapes different proteins make, we need lots of evidence that a folding model matches the true output of the mRNA. So yeah, I look forward to the day when we can truly predict how they fold, but it's going to take a lot of work to determine the ways that different amino acids interact and how the conformational shape changes due to different interactions throughout the process of elongation. Then if that wasn't enough, we'll need to also account for the different molecular chaperones that assist some proteins in finding a functional conformational structure. I'd like to see some of the Bioinformatics guys get into this type of research (if they're not already), I'm sure there's a brilliant Biochemist out there just waiting to team up with a programmer to create a simulation that can accurately fold any sequence of amino acids.

Re:Sounds Like A Lot Of People Here Are Really Sma (1)

Doomedsnowball (921841) | more than 8 years ago | (#14507326)

Yup, that's me. Been working toward that for ten years now. No joke.

Ice-Nine (1)

ddkilzer (79953) | more than 7 years ago | (#14504217)

I hope this isn't the first step on the way to creating Ice-Nine [] ! (0)

Anonymous Coward | more than 8 years ago | (#14505707)

Well, I guess you have to have your structure already determined. But you just send these guys a PDB and they turn it into a 3D model in glass.

Structure 30,000 times harder than sequence? (1)

sidles (735901) | more than 8 years ago | (#14506295)

Given that the Sanger institute has over a billion gene sequence on file, and (according to Wikipedia) the Protein Data Bank has about 30-odd thousand structures, and assuming that structure and sequence are of roughly equal scientific interest, can we conclude that determining a protein structure is 30,000 times harder than determining a gene sequence?

em, but ... if you know the dna (0)

Anonymous Coward | more than 8 years ago | (#14509027)

i thought if you knew the complete aminoacid sequence of some
dna you would get ROOT access? i mean doesn't the "a""t""g""c"("u") sequence
by threes define the sequence of the amino-acid and thus how
the protein will fold?
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