Different conformational responses of the β2-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline
Different conformational responses of the β2-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline
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DOI：
10.1093/nsr/nwaa284
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发表时间：
2021-09-01
影响因子：
20.6
通讯作者：
Tian, Changlin
中科院分区：
文献类型：
--
作者：
Yang, Fan;Ling, Shenglong;Tian, Changlin
G蛋白偶联受体（GPCR）负责大多数细胞质信号传导，以响应具有不同功效特征的细胞外配体。各种光谱技术已经确定，表现出不同功效的激动剂可以选择性地稳定受体的特定构象。然而，通过具有不同功效的配体活化GPCR-G蛋白复合物的结构基础尚未完全理解。为了更好地理解具有不同功效的配体差异调节受体和G蛋白构象的机制的结构基础，我们使用单粒子冷冻电子显微镜分别在3.26埃和3.80埃的分辨率下测定了与部分激动剂沙丁胺醇结合或与完全激动剂异丙肾上腺素结合的β（2）AR-G α（s）β γ的结构。β（2）AR-Gs-沙丁胺醇和β（2）AR-Gs-异丙肾上腺素复合物之间的结构比较表明，与异丙肾上腺素相比，沙丁胺醇的结合亲和力和功效降低，这可能归因于氢键相互作用减弱，正构结合口袋中疏水相互作用减弱以及TM 6中旋转异构体切换开关的不同构象变化。此外，与异丙肾上腺素相比，观察到β（2）AR和G α的细胞内环2或3（ICL 2或ICL 3）与沙丁胺醇结合的相互作用更强，这可能会降低沙丁胺醇激活的β（2）AR-Gs复合物中的磷酸化。从观察到的这些β 2 AR复合物之间的结构差异，提出了部分和完全激动剂激活β 2 AR的机制，以提供对β 2 AR脱敏的结构见解。
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 of beta(2)AR-G alpha(s)beta gamma bound with partial agonist salbutamol or bound with full agonist isoprenaline using single-particle cryo-electron microscopy at resolutions of 3.26 angstrom and 3.80 angstrom, respectively. Structural comparisons between the beta(2)AR-Gs-salbutamol and beta(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) of beta(2)AR and G alpha(s) with binding of salbutamol versus isoprenaline might decrease phosphorylation in the salbutamol-activated beta(2)AR-Gs complex. From the observed structural differences between these complexes of beta(2)AR, a mechanism of beta(2)AR activation by partial and full agonists is proposed to provide structural insights into beta(2)AR desensitization.