High-resolution structural snapshots of signaling intermediate states
GPCRs have a wealth of structural information; nearly 500 (largely crystal) structures of inactive states and nearly 1000 (largely cryoEM) structures of active, G-protein-bound states have been solved to date. Evidence from a wide array of techniques indicates that GPCRs occupy many conformations that are distinct from the “endpoint” fully inactive and fully active states. More importantly, receptor intermediate states are likely key to achieving the complex, multifaceted signaling outcomes that are the hallmark of GPCRs! The lab is developing methods dedicated to solving high-resolution cryoEM structures of receptors in the absence of stabilizing partner proteins or crystal contacts with the goal of detailing a broader structural landscape than has been observed thus far. Such states may serve as novel starting points in structure-based drug design strategies.