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I have spent months as a student working on trying to form a tricky protein crystal. But I have never actual had explained to me why the structure will be useful. Once elucidated, what can we potentially learn from the structure in terms of biological significance?

Generally speaking, why do people spend all the money on synchrotrons, laboratories, robots and so on, for a crystal structure?

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Out of curiosity, what is the protein/what does it do? If you don't mind me asking... –  Amory Oct 7 '13 at 14:28
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Awaiting publication so I can't give too much away, but the team is studying cardiac titin: a filamentous protein responsible for heart muscle elasticity. –  Good Gravy Oct 7 '13 at 23:08

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Protein structures, which can be obtained from protein crystals or from concentrated solutions of pure protein via NMR, are arguably the primary source of knowledge that we have about how genes perform their function on the molecular level.

I've added a link to RCSB.org above - they write up a story on an important protein structure monthly(?) - its a great way to pick up some fascinating stories.

The precise atomic positions from a protein structure are indispensible for several reasons. Since biological processes are all fundamentally chemical ones. The specific positions of the atoms reveal how proteins, nucleotides, lipids, drugs and other biological molecules specifically interact.

Examples:

  1. Protein structures broke the ground in biological inheritance (Watson / Crick / Franklin's DNA structure)
  2. Protein structures of lysozyme and proteases were the first to show exactly how proteins bind their substrates and enzymatically catalyze chemical reactions.
  3. Protein structure of hemoglobin in both oxy- and deoxy- forms (i.e. with and without oxygen bound). showed that proteins change their spatial arrangement to modulate their function.

This list goes on to more recent breakthroughs in how signals and molecules interact with the cell through the membrane. There is literally no topic in cellular biology which has not substantially benefitted from having a protein structure revealed.

The advantages of working with protein crystals are that they can be larger proteins and certain kinds of difference experiments an be more easily performed when a protein crystal is obtained. For instance if you have a crystal of a 100 kDa (~900 amino acid) protein, you can often find the binding pocket of the enzyme without a tremendous amount of work.

The disadvantage of working with protein crystals, as you probably know well is that getting crystals is often a quixotic effort soaking up months or years, often with little or no results. Pretty demoralizing until you hit the target.

If you're astounded to think that proteins, which are often hundreds or thousands of times larger than a salt or mineral you usually find in crystals...you are dead on. The crystals are often very tiny - a decent sized crystal measures about a millimeter on one side, but often are only a fraction of that size. That's why protein crystals often are taken to synchrotrons, linear accellerators or other free electron X-ray sources which are millions (?) of times more intense than a dental x-ray. I would guess that most protein crystal structures are obtained using special beamlines created especially for biological crystallography.

That sort of tells you the funding priority science is willing to put into x-ray protein crystal structures. Simply the idea that protein crystals might be easier to grow in microgravity (along with the low weight of the experiment) justified over a decade of protein crystal growth experiments on the shuttle and ISS.

Interesting note: The Guardian (which is based in the UK where crystallography, protein or otherwise started out) has posted a short video outlining highlights of crystallography's contributions over the past 100 years. If you watch assiduously you will see protein crystallography cropping up with a litany of nobel prizes.

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Having studied a little geology, I immediately thought of X-ray diffraction, but I could see how X-rays might be more problematic for proteins. Wikipedia's NMR crystallography article might be worth linking. –  Paul A. Clayton Oct 8 '13 at 0:11
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The method to stabilize the crystals since the early 90s has been to freeze the crystals with a stream of nitrogen at about liquid N2 temperatures. Since then, its been a lot easier to get good diffraction data. The hard part is still getting crystals in many cases tho. –  shigeta Oct 8 '13 at 13:59

I always wondered this myself, but the structure of a protein can end up being quite important for a number of reasons. Most relate to the fact that protein function often depends on specific domains, and while a protein may have multiple functional domains it is important for all domains to be properly aligned and constructed in three-dimensional space. Misfolded proteins often have negative phenotypes, so being able to visualize the improperly folded areas can be enlightening. Perhaps more commonly, these techniques can be used to validate an artificially produced protein before approving it for therapy.

Additionally, while we can know the sequence of amino acids in a protein very easily we don't necessarily know which ones are useful. A region oriented toward the outside of a protein may partake in a biological function. If a specific protein domain is imbedded inside the center of the protein, it is not very available for function, either by the protein or for other targets such as antibodies. For example, one of the big projects in HIV research now is to get very good and very fine structure of viral proteins on the envelope of the virus; knowing which regions are readily accessible would make for potential good drug/cell/antibody targets.

Finally, the structure itself can give some insight as to function. Proteins may not have homology by amino acid sequence, but similarly-structured proteins can have similar functions. People smarter than me can recognize those features and can learn quite a bit about a protein just from its shape.


Here's a fun little anecdote I conveniently just came upon. It's a quote from Your Inner Fish by Neil Shubin (© 2008) about two researchers, Linda Buck and Richard Axel, who in 1991 discovered a family of genes that allow us to smell.

Experiments showed that odor receptors have a characteristic structure with a number of molecular loops that help them convey information across a cell. This was a big clue, because Buck and Axel could then search the genome of a mouse for every gene that makes this structure.

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Expanding on something Amory said:

They are very beneficial in drug discovery. This is because it is absolutely essential that you have a structure to do any sort of molecular dynamic simulation. In the early phases of drug discovery it is cheap and easy to do these types of experiments on a computer, rather than setting up an assay for different potential therapeutics. You just take the crystal stucture of the protein, and a structure of your compound, and a program will simulate how they will interact with each other. From this you can see if the compound is able to enter the active site of the protein, the orientation it would be in, etc. Using a supercomputer you can do this with hundreds of compounds in a matter of hours. Molecular dynamics has other useful purposes, drug discovery is just one example.

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