Binding pathway determines norepinephrine selectivity for the human β 1 AR over β 2 AR.

Autor: Xu X; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.; School of Medicine, Tsinghua University, Beijing, 100084, China., Kaindl J; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany., Clark MJ; Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093, USA., Hübner H; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany., Hirata K; 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.; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan., Sunahara RK; Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093, USA. rsunahara@ucsd.edu., Gmeiner P; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany. peter.gmeiner@fau.de., Kobilka BK; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.; School of Medicine, Tsinghua University, Beijing, 100084, China.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA., Liu X; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China. liu_xy@mail.tsinghua.edu.cn.; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. liu_xy@mail.tsinghua.edu.cn.
Jazyk: angličtina
Zdroj: Cell research [Cell Res] 2021 May; Vol. 31 (5), pp. 569-579. Date of Electronic Publication: 2020 Oct 22.
DOI: 10.1038/s41422-020-00424-2
Abstrakt: Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β 1 AR and β 2 AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β 1 AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β 1 AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between β 1 AR and β 2 AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.
Databáze: MEDLINE
Externí odkaz: