小柯机器人

人类GABA B受体非活性状态结构获解析
2020-06-26 18:21
来源：小柯机器人

近日，美国哥伦比亚大学Qing R. Fan、Joachim Frank、Oliver B. Clarke等研究人员合作解析出人类GABAB受体处于非活性状态的结构。该项研究成果于2020年6月24日在线发表在《自然》杂志上。

研究人员报道了原子分辨率下的GAB B受体的近全长结构，该结构通过冷冻电镜以非活动状态捕获。这些结构揭示了几个与受体预结合的配体，包括两个大的内源性磷脂，它们嵌入跨膜结构域以维持受体的完整性并调节受体的功能。研究人员还确定了两个亚基的跨膜螺旋3和5之间未知的异二聚体界面，其作为非活性构象的特征。跨膜界面中独特的“亚基间闩锁”保持非活性状态，其破坏导致持续受体活性。
 
据介绍，人类GABAB受体是G蛋白偶联受体（GPCR）C类家族的成员，可介导抑制性神经传递，并与癫痫、疼痛和成瘾有关。GABAB受体是一种独特的GPCR，已知需要异二聚化才能实现功能，它具有两个亚基GABAB1和GABAB2，它们在结构上是同源的，但执行不同的互补功能。GABAB1识别正构配体，而GABAB2与G蛋白偶联。每个亚基的特征是一个胞外VFT（Venus flytrap）模块、一个多肽衔接子、一个七螺旋跨膜结构域以及一个胞质尾巴。尽管VFT异二聚体结构已得到解析，但全长受体的结构及其跨膜信号传导机制仍然未知。
 
附：英文原文

Title: Structure of human GABA B receptor in an inactive state

Author: Jinseo Park, Ziao Fu, Aurel Frangaj, Jonathan Liu, Lidia Mosyak, Tong Shen, Vesna N. Slavkovich, Kimberly M. Ray, Jaume Taura, Baohua Cao, Yong Geng, Hao Zuo, Yongjun Kou, Robert Grassucci, Shaoxia Chen, Zheng Liu, Xin Lin, Justin P. Williams, William J. Rice, Edward T. Eng, Rick K. Huang, Rajesh K. Soni, Brian Kloss, Zhiheng Yu, Jonathan A. Javitch, Wayne A. Hendrickson, Paul A. Slesinger, Matthias Quick, Joseph Graziano, Hongtao Yu, Oliver Fiehn, Oliver B. Clarke, Joachim Frank, Qing R. Fan

Issue&Volume: 2020-06-24

Abstract: The human GABAB receptor—a member of the class C family of G-protein-coupled receptors (GPCRs)—mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2,3,4,5,6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9,10,11,12,13,14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor at atomic resolution, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique ‘intersubunit latch’ within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

DOI: 10.1038/s41586-020-2452-0

Source: https://www.nature.com/articles/s41586-020-2452-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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