Donald Raymond solves the structures of proteins and supports the development of better therapeutics
Growing up in St. Lucia, a small island in the Caribbean, Donald Raymond explored the world through books. He was especially fond of science fiction—the more scientifically accurate the better—and Michael Crichton’s books became his favorite. But reading about science didn’t fully satisfy Raymond’s curiosity. He wanted to discover for himself how things in the natural world worked—a desire that led him to study biological chemistry. Now a research scientist in the Broad Institute’s Center for the Development of Therapeutics, Raymond uses X-ray crystallography to answer important questions about protein structures and support drug development.
He spoke with us about his work in a #WhyIScience Q&A:
Q: Can you describe what you do in your research?
A: As an X-ray crystallographer, I determine high-resolution, three-dimensional structures of proteins and protein-ligand complexes. This accelerates the development of highly-specific drug-like molecules with fewer side effects.
Q: What drew you to X-ray crystallography?
A: I’ve always been interested in how nature works at the molecular level and always experimented and tinkered whenever the opportunity arose. I discovered X-ray crystallography in graduate school and it was love at first sight. I just didn’t believe you could do it. You take a protein and you make a crystal out of it. Then you hit it with an intense X-ray beam and you get all this diffraction. Then that goes back to a 3D structure that lets you visualize the location of every atom in the molecule. It’s great when you have a structure of the entire protein because then you know how the protein is built, you know how it interacts with its partners, and you know how it functions. You get this clarity that you can’t get anywhere else. There were questions that researchers have been asking for years or decades, but once you get a structure the answer becomes completely obvious.
Q: As a member of the Center for the Development of Therapeutics, how do you and your team fit into the bigger picture of drug development?
A: Our goal is to optimize the drug-like molecules we currently have by increasing their safety, potency and specificity to treat disease. X-ray crystallography is critical to that mission because it enables us to visualize how the changes we make to the drug affect the way it fits in the binding site.
Q: Can you explain what a binding site is?
A: Whenever a protein interacts with another protein or a substrate, it does so through this region known as the binding site. Typically, most of the protein is a scaffold for this one site. If you make changes to the protein you will change or block that site. How that relates to drug discovery is that with many therapeutic projects, you want to disrupt that binding site so that the proteins don’t interact or function. In some cancers, for example, certain enzymes are up-regulated and hyperactive, so designing a compound that inactivates the enzyme by blocking the binding site may lead to cancer cell death.
Q: What are the biggest challenges in your field right now?
A: The challenge faced by all Broadies: storing, managing, and processing large quantities of data. Over the past few years, there has been an exponential increase in the amount of data we collect as a direct result of improved crystallographic methods, faster detectors, automated data collection, and fragment-based screening in crystals. We are still finding ways to sort through that mountain of data so our project team can accelerate the optimization of promising compounds.
Q: What, in your opinion, has been your biggest scientific accomplishment to date?
A: Solving the structure of an important drug target that eluded academic and industrial labs for decades. It’s a challenging target because it’s very difficult to make the protein and consequently hard to crystallize it. I was able to solve the structure, which was very cool, but we weren’t able to use it in its original form, so I had to come up with some tricks to get it to a state where we could use it. Since we solved that structure, we have made significant headway in terms of finding an inhibitor that does precisely what we want it to do.