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Science. 2019 Jun 28;364(6447):1283-1287. doi: 10.1126/science.aaw8981. Epub 2019 Jun 27.

Mechanism of β2AR regulation by an intracellular positive allosteric modulator.

Author information

1
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
2
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
3
Advanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center, 1-1-1 Kouto Sayo-cho Sayo-gun, Hyogo 679-5148, Japan.
4
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
5
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. lefko001@receptor-biol.duke.edu kobilka@stanford.edu.
6
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
7
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
8
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. lefko001@receptor-biol.duke.edu kobilka@stanford.edu.
9
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.

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 β2-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 α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β2- over the β1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.

PMID:
31249059
DOI:
10.1126/science.aaw8981

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