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

Autor: Xiangyu Liu, Ali Masoudi, Alem W. Kahsai, Li-Yin Huang, Biswaranjan Pani, Dean P. Staus, Paul J. Shim, Kunio Hirata, Rishabh K. Simhal, Allison M. Schwalb, Paula K. Rambarat, Seungkirl Ahn, Robert J. Lefkowitz, Brian Kobilka
Rok vydání: 2019
Předmět:
Zdroj: Science. 364:1283-1287
ISSN: 1095-9203
0036-8075
DOI: 10.1126/science.aaw8981
Popis: Positive reinforcement in a GPCR Many drug discovery efforts focus on G protein–coupled receptors (GPCRs), a class of receptors that regulate many physiological processes. An exemplar is the β 2 -adrenergic receptor (β 2 AR), which is targeted by both blockers and agonists to treat cardiovascular and respiratory diseases. Most GPCR drugs target the primary (orthosteric) ligand binding site, but binding at allosteric sites can modulate activation. Because such allosteric sites are less conserved, they could possibly be targeted more specifically. Liu et al. report the crystal structure of β 2 AR bound to both an orthosteric agonist and a positive allosteric modulator that increases receptor activity. The structure suggests why the modulator compound is selective for β 2 AR over the closely related β 1 AR. Furthermore, the structure reveals that the modulator acts by enhancing orthosteric agonist binding and stabilizing the active conformation of the receptor. Science , this issue p. 1283
Databáze: OpenAIRE
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