Journal Article

Functional and structural basis of a negative allostery within GABA B hetero-tetramers

Zhou, Rui, Zhang, Shenlan, Rondard, Philippe, Chen, Xuan, He, Jun, Shen, Dan-Dan, Liu, Jianfeng, Shen, Cangsong, Liang, Jiayin, Ji, Suyu, Li, Yizhong, Liu, Yi-Ru, Zou, Binqian, Pin, Jean-Philippe, Xu, Chanjuan, Zhang, Yan, Liu, Yuxuan, Ding, Hongyang

2026

Overview

G protein coupled receptors (GPCRs) oligomerization may allow signal integration from different GPCR units. The GABA receptor, activated by the main inhibitory transmitter, GABA, is an obligatory heterodimer. It is the target of two therapeutic drugs, baclofen and GHB, and can form stable oligomers. The existence, roles, and possible allosteric interaction of GABA oligomers remain elusive. Here, we show that GABA oligomers exist in neurons. Their function can be specifically affected by human disease-associated mutations, demonstrating their essential role for normal brain function. The cryo-EM structure of a hetero-tetramer in the apo state reveals the heterodimers interacting in an asymmetrical way to prevent one unit from being activated. This represents a nice example of a negative allosteric interaction between GPCRs related to human diseases.