Illuminating Pharmacologically Dark Neuronal GPCR Signaling by Cryo-EM
EMSL Project ID
51817
Abstract
G protein-coupled receptors (GPCRs) are critically important regulators of human physiology and represent an outsized fraction of currently approved therapeutics. Over the past few years, cryo-EM of GPCRs has enabled structural interrogation of many receptors, paving the path for structure-enabled discovery of transformative therapeutics. In the face of such success is the lack of structural understanding of most “orphan” GPCRs – receptors for which either the endogenous agonist is unknown, or for which there are almost no tool compounds to interrogate their function. We have recently developed new approaches to purify orphan GPCRs for structural analysis by cryo-EM. We combined these approaches with new strategies to make transmembrane GPCRs amenable to high-resolution structure determination by cryo-EM. Here, we focus on two orphan GPCRs important in neurobiology - we propose to determine structures of these receptors to either understand regulation by proposed endogenous stimuli, or to discover potential ligands. More broadly, successful implementation of the approaches outlined in this proposal will enable structure determination for many other orphan GPCRs, potentially unlocking the immense potential of these imminently druggable, but thus far intractable, targets.
Project Details
Start Date
2021-02-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members