An allosteric modulator binds to a conformational hub in the β₂ adrenergic receptor.

ABSTRACT: Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the β₂-adrenergic receptor (β₂AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E122^3.41 and the backbone carbonyls of V206^5.45 and S207^5.46. The AS408 binding site is adjacent to a previously identified molecular switch for β₂AR

SUBMITTER: Liu X 

PROVIDER: S-EPMC7816728 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature