Mechanism of β2AR regulation by an intracellular positive allosteric modulator.
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.
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
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