6n48

Publication Abstract from PubMed

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 beta2-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 alpha-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for beta2- over the beta1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.

Mechanism of beta2AR regulation by an intracellular positive allosteric modulator.,Liu X, Masoudi A, Kahsai AW, Huang LY, Pani B, Staus DP, Shim PJ, Hirata K, Simhal RK, Schwalb AM, Rambarat PK, Ahn S, Lefkowitz RJ, Kobilka B Science. 2019 Jun 28;364(6447):1283-1287. doi: 10.1126/science.aaw8981. Epub 2019, Jun 27. PMID:31249059^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.