Computational characterization of transducer recognition of β2 adrenergic receptor

Lifen Zhao; Xinheng He; Hualiang Jiang; Xi Cheng

doi:10.1016/j.bbrc.2022.01.012

Computational characterization of transducer recognition of β2 adrenergic receptor

Biochem Biophys Res Commun. 2022 Feb 12:592:67-73. doi: 10.1016/j.bbrc.2022.01.012. Epub 2022 Jan 7.

Authors

Lifen Zhao¹, Xinheng He², Hualiang Jiang³, Xi Cheng⁴

Affiliations

¹ State Key Laboratory of Drug Research and Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² State Key Laboratory of Drug Research and Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
³ State Key Laboratory of Drug Research and Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, 310024, China. Electronic address: hljiang@simm.ac.cn.
⁴ State Key Laboratory of Drug Research and Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, 310024, China. Electronic address: xicheng@simm.ac.cn.

PMID: 35032834
DOI: 10.1016/j.bbrc.2022.01.012

Abstract

As an important drug target, β2 adrenergic receptor (B2AR) regulates many physiological processes, including cardiac function, airway tone and metabolic functions. The selective coupling between B2AR and specific transducers is critical for the physiological action of the receptor. However, the molecular mechanism by which B2AR recognizes different transducers remains elusive. Here, molecular dynamics simulations of B2AR binding to three functionally important transducers (Gs, Gi and β-arrestin 1) unveiled distinct binding modes of the receptor. Involving transmembrane helices TMs 2-7 and intracellular loops ICLs 2-3, different binding interfaces for Gs and β-arrestin 1 were identified in the simulation models and further validated by various assays. The distinct recognition mode of B2AR for Gi was computationally characterized. Insights into receptor-transducer communication not only enhance our understanding of signaling bias, but also offer hints for rational drug design targeting specific signaling pathways of G-protein coupled receptors (GPCRs).

Keywords: Class A G-protein coupled receptor; Complex models; Coupling selectivity; Functional signal; Transducer-binding interface.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Computer Simulation*
GTP-Binding Proteins / chemistry
GTP-Binding Proteins / metabolism
HEK293 Cells
Humans
Molecular Dynamics Simulation
Protein Binding
Receptors, Adrenergic, beta-2 / chemistry
Receptors, Adrenergic, beta-2 / metabolism*
Signal Transduction*
beta-Arrestin 1 / metabolism

Substances

Receptors, Adrenergic, beta-2
beta-Arrestin 1
GTP-Binding Proteins