Dr. Alexander Sobolevsky
My lab studies structure and function of ion channels, including ionotropic glutamate receptors (iGluRs) and transient receptor potential (TRP) channels, using a combination of biochemical and biophysical methods and cryo-electron microscopy (cryo-EM) in particular. I have an expertise in solving structures of integral membrane proteins by both X-ray crystallography and cryo-EM and an extensive experience in using methods of characterizing ion channels function, including patch-clamp, double-electrode voltage-clamp recordings and Fura-2-based ratiometric fluorescent measurements of intracellular calcium. I also have an expertise in analyzing different types of ion channel inhibition using a combination of electrophysiology, protein engineering and kinetic modeling. With such expertise and experiences, I studied the mechanisms of ionotropic glutamate receptor (iGluR) inhibition by ion channel blockers, including the only FDA-approved NMDA receptor channel blocker Memantine, currently used for treatment of Alzheimer’s disease. I solved the first full length crystal structure of ionotropic glutamate receptor. My lab solved numerous structures of full-length iGluRs, including the first agonist-bound, open and desensitized state structures and proposed the first complete structural model of iGluR gating. Using X-ray crystallography, my lab determined the structural mechanism of iGluR inhibition by noncompetitive inhibitors, including Perampanel that is currently used for treatment of epilepsy. My lab also solved the first TRP channel crystal structure (the structure of TRPV6). Using cryo-EM, my lab determined structures of human TRPV6 in different conformations and proposed the mechanism of TRPV6 activation. Similarly, my lab solved the first TRPV3 structure and structures of TRPV3 in different conformations and proposed the mechanism of ligand-induced TRPV3 activation. Recently, we solved structures of TRPV3 in temperature-dependent closed, intermediate and open states, which for the first time uncovered the structural bases of TRP channel activation by temperature. As a result of my previous experiences, I am aware of the importance of frequent communication among project members and of constructing a realistic research plan, timeline, and budget. My current research plans build logically on my prior work.