Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR

Xu X, Kaindl J, Clark MJ, Hübner H, Hirata K, Sunahara RK, Gmeiner P, Kobilka BK, Liu X (2021)

Publication Type: Journal article, Original article

Publication year: 2021

Journal

Cell Research Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 31

Pages Range: 569-579

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.

Authors with CRIS profile

Jonas Kaindl Lehrstuhl für Pharmazeutische Chemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

University of California, San Diego US United States (USA) (US) Riken Institute of Physical and Chemical Research / 理研 JP Japan (JP) Tsinghua University CN China (CN)

How to cite

APA:

Xu, X., Kaindl, J., Clark, M.J., Hübner, H., Hirata, K., Sunahara, R.K.,... Liu, X. (2021). Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR. Cell Research, 31, 569-579. https://dx.doi.org/10.1038/s41422-020-00424-2

MLA:

Xu, Xinyu, et al. "Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR." Cell Research 31 (2021): 569-579.

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