Functional and structural basis of a negative allostery within GABAB hetero-tetramers
Cangsong Shen1,2, Hongyang Ding1,2, Shenlan Zhang2
1Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China.
Abstract:
G protein coupled receptors (GPCRs) oligomerization may allow signal integration from different GPCR units. The GABAB 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 GABAB oligomers remain elusive. Here, we show that GABAB 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.
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