In Situ Structural Biology
Protein structures provide clues to the mechanisms of biological processes and essential inspiration for new hypotheses. Yet little is known about how protein structures behave inside cells, because it is very difficult to make high‑resolution measurements in the cellular environment. This is a fundamental unsolved problem in biochemistry. With Josh Elias' lab, we have developed techniques to record the conformational state of a protein in the form of covalent bonds, and then to read out this information by high-throughput mass spectrometry. With Raj Rohatgi's lab, we are applying these techniques in live cells to understand how changes in the structure of transmembrane receptors (for example the Smoothened receptor) transduce signals across the plasma membrane. Our aspiration is to create a powerful and efficient tool for analyzing large molecular machines, and to unify cell biology, proteomics and structural analysis. This project combines creative chemistry, rewiring of the genetic code, and advances in computational structure prediction.