What do structural biologists do?

Structural biologists are best known for taking molecular “pictures” of proteins and other macromolecules (using methods like x-ray crystallography and cryo electron microscopy (cryoEM)). But that’s just one part of their work. The real fun in my opinion comes from using follow-up biochemistry experiments to study what those “pictures” reveal about how the molecules’ form (structure) relates to their functions. But to do all this cool stuff, you typically need a lot of really pure protein. So a huge part of most structural biology is expressing and purifying proteins! And lots of optimization and troubleshooting to try to get cooperative proteins! Although parts of the job require a lot of “dry,” computational work to generate and refine the atomic models of the proteins, etc. you want to look at, be prepared to spend a lot of time at the bench getting messy with “wet work!”

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Note: some people in structural biology labs specialize more in specific aspects so they might only deal with the computational parts or the biochemistry parts, etc. but for lots of structural biologists, especially when training, they do it all. Or, in some cases one person will do the expression and purification and hand it off to another person, potentially in a different lab, who will do the actual structural determination part (collect and analyze data using crystallography, cryo-EM, etc.). Collaborating like this can be a huge win for both! And for the public at large because it allows us to capitalize on various labs’ diverse expertise and interests to get structures of a huge variety of molecules.

Note: I did my PhD in a structural biology lab (Dr. Leemor Joshua-Tor’s lab at Cold Spring Harbor Laboratories) and did some crystallography but mainly focused on the biochemistry side of things. But I like being structurally-adjacent! And have a deep appreciation for the structural parts of structural biology even though I prefer to leave the structure determination to others. So I deeply appreciate the people who prefer to do that side of things! But back to the story…

So, say you solve the structure (figure out the position of the atoms making up that protein, etc.) Now what?

You can learn a lot about how a protein works by seeing what it looks like (imagine seeing a picture of an open Swiss army knife). And you can also learn about how a protein might “not work” if you can tie up or hide certain parts with another molecule, like a pharmaceutical drug. There’s a lot you can learn from structures and a lot of hypotheses you can generate, but you also need some experimental proof to see whether your ideas pan out. So a big part of structural biology is doing biochemistry and biophysics-type experiments in the lab (as well as sometimes cell-based experiments, often in collaboration with other labs) to test them.

Thanks to molecular biology, we can use site-directed mutagenesis to introduce specific mutations to the genetic recipes for making the proteins, introducing changes to the resulting proteins. We can make changes parts of the protein that the structure suggests are important for something and then see whether doing so screws up that “something” (but make sure you don’t just screw up protein folding or something else in the process!)
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Going back to our Swiss army knife analogy, it’s like if you see a corkscrew and you want to prevent people from de-corking bottles you could file down the point of the screw so people couldn’t get it into the cork.

So these structure-directed mutations can help us work out how molecules work. And they also can help us see how we might be able to prevent them from working! We might want to do this to tamp down a hyperactive protein that’s causing a disease or to inactivate a viral protease (protein cutter) to prevent it from making more virus.

You’re not going to be able to mutate* a protein inside an actual person, but you can introduce pharmaceutical drugs that bind to the site! And knowing what that site looks like can help.

Similarly to how you could design a “cap” that covers up the pointy tip of the corkscrew, if you can see what a protein’s “active site” looks like, the part where the protein “does stuff” (e.g. the place in a viral protease where it grabs onto and cuts proteins), you can better design a drug that binds there and blocks it. Instead of designing from scratch, scientists often start by using crystallography to screen pre-existing drugs (some of which are already approved for treating other diseases) through a compound library screen, or screening pieces (a fragment screen). Once they get hits they can then look closely at how it interacts with the protein and how they might be able to alter the molecule to bind better. More here: https://bit.ly/mproinhibitors

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