Cryo-EM as a tool for illuminating activation mechanisms of human class A orphan GPCRs

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100056 - 100056

Published: April 1, 2025

G protein-coupled receptors (GPCRs) are critically important medicinal targets, and the cryogenic electron microscopy (cryo-EM) revolution is providing novel high-resolution GPCR structures at a rapid pace. Orphan (oGPCRs) group of approximately 100 nonolfactory GPCRs for which endogenous ligands unknown or not validated. The absence modulating adds difficulties to understanding physiologic significance oGPCRs in determination isolated that could facilitate drug discovery. Despite challenges, cryo-EM oGPCR-G protein complexes emerging. This being facilitated by numerous developments stabilize GPCR-G such as use dominant-negative proteins, mini-G complex-stabilizing nanobodies antibody fragments, tethering methods. Moreover, many constitutively active, can complex formation known activating ligand. Consequently, addition templates discovery, active oGPCR shed light on constitutive activation mechanisms. These comprise self-activation, whereby mobile extracellular portions receptor act tethered agonists occupying canonical orthosteric-binding site transmembrane core, activity due alterations conserved molecular switches inactive states GPCRs, well activated cryptic copurified with receptor. Cryo-EM now determined pace expected be invaluable tools SIGNIFICANCE STATEMENT: provide large untapped potential development new medicines. Many these display activity, enabling structure insights into observed including (1) self-activation function agonists, (2) modification motifs canonically involved quiescence and/or activation, (3) lipid ligands. Collectively, studies advance fundamental opportunities

Language: Английский

Unraveling the proton-sensing mechanisms of G protein-coupled receptors: Insights from cryogenic electron microscopy studies

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(8), P. 1479 - 1481

Published: April 1, 2025

Language: Английский