An allosteric modulator binds to a conformational hub in the β 2 adrenergic receptor.

Autor: Liu X; School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China., Kaindl J; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Korczynska M; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA., Stößel A; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Dengler D; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Stanek M; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Hübner H; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany., Clark MJ; Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA., Mahoney J; Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA., Matt RA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Xu X; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China.; School of Medicine, Tsinghua University, Beijing, China., Hirata K; Advanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center Sayo-gun, Hyogo, Japan.; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan., Shoichet BK; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA., Sunahara RK; Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA. rsunahara@ucsd.edu., Kobilka BK; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China. kobilka@stanford.edu.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.; School of Medicine, Tsinghua University, Beijing, China. kobilka@stanford.edu., Gmeiner P; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. peter.gmeiner@fau.de.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2020 Jul; Vol. 16 (7), pp. 749-755. Date of Electronic Publication: 2020 Jun 01.
DOI: 10.1038/s41589-020-0549-2
Abstrakt: 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 β 2 -adrenergic receptor (β 2 AR), 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 β 2 AR activation formed by I 3.40 , P 5.50 and F 6.44 . The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.
Databáze: MEDLINE
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