2. Academic Validation
  3. Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR

Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR

  • Cell Res. 2021 May;31(5):569-579. doi: 10.1038/s41422-020-00424-2.
Xinyu Xu  # 1 2,  Jonas Kaindl  # 3,  Mary J Clark  # 4,  Harald Hübner 3,  Kunio Hirata 5 6,  Roger K Sunahara 7,  Peter Gmeiner 8,  Brian K Kobilka 1 2 9,  Xiangyu Liu 10 11
Affiliations

Affiliations

  • 1 Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.
  • 2 School of Medicine, Tsinghua University, Beijing, 100084, China.
  • 3 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany.
  • 4 Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
  • 5 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.
  • 6 Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
  • 7 Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093, USA. rsunahara@ucsd.edu.
  • 8 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany. peter.gmeiner@fau.de.
  • 9 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 10 Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China. liu_xy@mail.tsinghua.edu.cn.
  • 11 School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. liu_xy@mail.tsinghua.edu.cn.
  • # Contributed equally.
PMID: 33093660 DOI: 10.1038/s41422-020-00424-2
Abstract

Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β1AR and β2AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β1AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β1AR 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 β1AR and β2AR, 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.

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