Mechanism of β2AR regulation by an intracellular positive allosteric modulator.

Journal Article (Journal Article)

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 α-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.

Full Text

Duke Authors

Cited Authors

  • Liu, X; Masoudi, A; Kahsai, AW; Huang, L-Y; Pani, B; Staus, DP; Shim, PJ; Hirata, K; Simhal, RK; Schwalb, AM; Rambarat, PK; Ahn, S; Lefkowitz, RJ; Kobilka, B

Published Date

  • June 28, 2019

Published In

Volume / Issue

  • 364 / 6447

Start / End Page

  • 1283 - 1287

PubMed ID

  • 31249059

Pubmed Central ID

  • PMC6705129

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

Digital Object Identifier (DOI)

  • 10.1126/science.aaw8981


  • eng

Conference Location

  • United States