Constrained catecholamines gain β 2 AR selectivity through allosteric effects on pocket dynamics.

Autor: Xu X; State Key laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.; Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China., Shonberg J; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nurnberg, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, Germany., Kaindl J; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nurnberg, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, Germany., Clark MJ; Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, USA., Stößel A; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nurnberg, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, Germany., Maul L; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nurnberg, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, Germany., Mayer D; Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, USA., Hübner H; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nurnberg, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, 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., Venkatakrishnan AJ; Department of Computer Science, Stanford University, Stanford, CA, 94305, USA.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, 94305, USA., Dror RO; Department of Computer Science, Stanford University, Stanford, CA, 94305, USA.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, 94305, USA., Kobilka BK; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA. kobilka@stanford.edu., Sunahara RK; Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, USA. rsunahara@health.ucsd.edu., Liu X; State Key laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. liu_xy@mail.tsinghua.edu.cn.; Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China. liu_xy@mail.tsinghua.edu.cn.; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China. liu_xy@mail.tsinghua.edu.cn., Gmeiner P; Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nurnberg, Nikolaus-Fiebiger-Straße 10, 91058, Erlangen, Germany. peter.gmeiner@fau.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 14; Vol. 14 (1), pp. 2138. Date of Electronic Publication: 2023 Apr 14.
DOI: 10.1038/s41467-023-37808-y
Abstrakt: G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β 1 and β 2 adrenergic receptors (β 1 AR and β 2 AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β 2 AR over the β 1 AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β 2 AR, as well as a less stable binding pocket for constrained epinephrine in the β 1 AR. The differences in the amino acid sequence of the extracellular vestibule of the β 1 AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β 2 AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.
(© 2023. The Author(s).)
Databáze: MEDLINE
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