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
Science, 2019, 364, 6447, 1283-1287
https://doi.org/10.1126/science.aaw8981

Abstract

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