Volume 31, No 5, May 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 5, May 2021: 569-579

ORIGINAL ARTICLES

Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR

Xinyu Xu^1,2 , Jonas Kaindl³ , Mary J. Clark⁴ , Harald Hübner³ , Kunio Hirata^5,6 , Roger K. Sunahara^4,* , Peter Gmeiner^3,* , Brian K. Kobilka^1,2,7 , Xiangyu Liu^1,8,*

¹Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
²School of Medicine, Tsinghua University, Beijing 100084, China
³Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich–Alexander University Erlangen–Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen 91058, Germany
⁴Department of Pharmacology, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA
⁵Advanced 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
⁶Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
⁷Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA
⁸School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
These authors contributed equally: Xinyu Xu, Jonas Kaindl, Mary J. Clark Correspondence: Roger K. Sunahara(rsunahara@ucsd.edu)Peter Gmeiner(peter.gmeiner@fau.de)Xiangyu Liu(liu_xy@mail.tsinghua.edu.cn)

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.

https://doi.org/10.1038/s41422-020-00424-2

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