Apr 22, 2020

Cryo-EM structures of inactive and Gi-coupled GABAB heterodimer

BioRxiv : the Preprint Server for Biology
C. MaoY. Zhang

Abstract

Metabotropic GABAB G protein-coupled receptor functions as a mandatory heterodimer of GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system. Each subunit is composed of the extracellular Venus flytrap (VFT) domain and transmembrane (TM) domain. Here we present cryo-EM structures of human full-length heterodimeric GABAB receptor in the antagonist-bound inactive state and in the active state complexed with agonist and positive allosteric modulator in the presence of Gi1 protein at a resolution range of 2.8-3.0 [A]. Cryo-EM analysis of the activated-GABAB-Gi1 complex revealed that Gi1 couples to the activated receptor primarily in three major conformations, one via GB1 TM and two via GB2 TM, respectively. Our structures reveal that agonist binding stabilizes the closure of GB1 VFT, which in turn triggers a rearrangement of TM interfaces between two subunits from TM3-TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the opening of intracellular loop 3 and synergistically shifting of TM3, 4 and 5 helices in GB2 TM domain to accommodate the 5-helix of Gi1. These results provide a structural framework for understanding class C GPCR activation and a rational temp...Continue Reading

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Mentioned in this Paper

Neurons
Brain
Figure Ground Perception
Structure of Cortex of Kidney
Entire Brodmann Areas 17 (Striate Cortex),18 (Parastriate Cortex) and 19 (Peristriate Cortex) of Occipital Lobe
Cellular Component Organization
Cerebral Cortex
Macaca mulatta
Organizational Groups
Visual Cortex

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