Mechanism of ?2AR regulation by an intracellular positive allosteric modulator.

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 ?2-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 ?-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for ?2- over the ?1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.

SUBMITTER: Liu X 

PROVIDER: S-EPMC6705129 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature