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

• Published in: Science (American Association for the Advancement of Science) Vol. 364; no. 6447; pp. 1283 - 1287
• Main Authors: Liu, Xiangyu, Masoudi, Ali, Kahsai, Alem W, Huang, Li-Yin, Pani, Biswaranjan, Staus, Dean P, Shim, Paul J, Hirata, Kunio, Simhal, Rishabh K, Schwalb, Allison M, Rambarat, Paula K, Ahn, Seungkirl, Lefkowitz, Robert J, Kobilka, Brian
• Format: Journal Article
• Language: English
• Published: United States 28.06.2019
• Subjects: Adrenergic beta-2 Receptor Agonists - chemistry; Adrenergic beta-2 Receptor Agonists - pharmacology; Allosteric Regulation; Crystallography, X-Ray; Gain of Function Mutation; Humans; Phthalic Anhydrides - chemistry; Phthalic Anhydrides - pharmacology; Receptors, Adrenergic, beta-2 - chemistry; Receptors, Adrenergic, beta-2 - genetics
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaw8981

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 β -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 α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β - over the β -adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.