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

Xiangyu Liu | Zendy; Ali Masoudi | Zendy; Alem W. Kahsai | Zendy; Li-Yin Huang | Zendy; Biswaranjan Pani | Zendy; Dean P. Staus | Zendy; Paul J. Shim | Zendy; Kunio Hirata | Zendy; Rishabh K. Simhal | Zendy; Allison M. Schwalb | Zendy; Paula Rambarat | Zendy; Seungkirl Ahn | Zendy; Robert J. Lefkowitz | Zendy; Brian K. Kobilka | Zendy

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

Author(s) -

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 Rambarat,

Seungkirl Ahn,

Robert J. Lefkowitz,

Brian K. Kobilka

Publication year - 2019

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aaw8981

Subject(s) - allosteric regulation , allosteric modulator , g protein coupled receptor , agonist , chemistry , receptor , intracellular , inverse agonist , binding site , ligand (biochemistry) , biophysics , drug discovery , pharmacology , microbiology and biotechnology , biochemistry , biology

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 β2 -adrenergic receptor (β2 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. Liuet al. report the crystal structure of β2 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 β2 AR over the closely related β1 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

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