Mechanism of β 2 AR regulation by an intracellular positive allosteric modulator

• DOI: 10.1126/science.aaw8981
• Publication Date: 2019-06-27T23:05:34Z
• Authors: Xiangyu Liu; Ali Masoudi; Alem W. Kahsai; Li-Yin Huang; Biswaranjan Pani; Dean P. Staus; Paul J. Shim; Kunio Hirata; Rishabh K. Simhal; Allison M. Schwalb; Paula K. Rambarat; Seungkirl Ahn; Robert J. Lefkowitz; Brian Kobilka
• Keywords: Allosteric modulator; Inverse agonist

Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are most common therapeutics. Allosteric sites, elsewhere on receptors, less well-defined, and so exploited clinically. We report crystal structure prototypic β2-adrenergic receptor in complex with an orthosteric agonist compound-6FA, a positive allosteric modulator this receptor. It binds receptor's inner surface pocket created by intracellular loop 2 transmembrane segments 3 4, stabilizing α-helical conformation required to engage protein. Structural comparison explains selectivity compound for β2- over β1-adrenergic Diversity location, mechanism, ligands provides potential expand range drugs.