Different conformational responses of theβ_(2)-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline  

作　　者：Fan Yang Shenglong Ling Yingxin Zhou Yanan Zhang Pei Lv Sanling Liu Wei Fang Wenjing Sun Liaoyuan A.Hu Longhua Zhang Pan Shi Changlin Tian 

机构地区：[1]Hefei National Laboratory of Physical Sciences at Microscale and School of Life Sciences,University of Science and Technology of China,Hefei 230026,China [2]Amgen Asia R&D Center,Amgen Research,Shanghai 201210,China [3]High Magnetic Field Laboratory,Chinese Academy of Sciences,Hefei 230030,China

出　　处：《National Science Review》2021年第9期106-115,共10页国家科学评论（英文版）

基　　金：supported by the National Key Research and Development Project of China(2016YFA0400903 to C.L.and2017YFA0505400 to P.S.);the National Natural Science Foundation of China(21825703 to C.L.and 31971152 to P.S.);the Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(2018CXFX004)。

摘　　要：G protein-coupled receptors(GPCRs)are responsible for most cytoplasmic signaling in response to extracellular ligands with different efficacy profiles.Various spectroscopic techniques have identified that agonists exhibiting varying efficacies can selectively stabilize a specific conformation of the receptor.However,the structural basis for activation of the GPCR-G protein complex by ligands with different efficacies is incompletely understood.To better understand the structural basis underlying the mechanisms by which ligands with varying efficacies differentially regulate the conformations of receptors and G proteins,we determined the structures ofβ_(2)AR-Gαsβγbound with partial agonist salbutamol or bound with full agonist isoprenaline using single-particle cryo-electron microscopy at resolutions of 3.26?A and3.80?A,respectively.Structural comparisons between theβ_(2)AR-Gs-salbutamol andβ_(2)AR-Gs-isoprenaline complexes demonstrated that the decreased binding affinity and efficacy of salbutamol compared with those of isoprenaline might be attributed to weakened hydrogen bonding interactions,attenuated hydrophobic interactions in the orthosteric binding pocket and different conformational changes in the rotamer toggle switch in TM6.Moreover,the observed stronger interactions between the intracellular loop 2 or 3(ICL2 or ICL3)ofβ_(2)AR and Gαswith binding of salbutamol versus isoprenaline might decrease phosphorylation in the salbutamol-activatedβ_(2)AR-Gs complex.From the observed structural differences between these complexes ofβ_(2)AR,a mechanism ofβ_(2)AR activation by partial and full agonists is proposed to provide structural insights intoβ_(2)AR desensitization.

关 键 词：cryo-EM structure G protein-coupled receptor(GPCR) partial and full agonists conformational change DESENSITIZATION 

分 类 号：R341[医药卫生—基础医学]