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

Allosteric modulator Inverse agonist
DOI: 10.1126/science.aaw8981 Publication Date: 2019-06-27T23:05:34Z
ABSTRACT
Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are most common therapeutics. Allosteric sites, elsewhere on receptors, less well-defined, and so exploited clinically. We report crystal structure prototypic β2-adrenergic receptor in complex with an orthosteric agonist compound-6FA, a positive allosteric modulator this receptor. It binds receptor's inner surface pocket created by intracellular loop 2 transmembrane segments 3 4, stabilizing α-helical conformation required to engage protein. Structural comparison explains selectivity compound for β2- over β1-adrenergic Diversity location, mechanism, ligands provides potential expand range drugs.
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