期刊
SCIENCE BULLETIN
卷 68, 期 1, 页码 95-104出版社
ELSEVIER
DOI: 10.1016/j.scib.2022.12.023
关键词
G protein-coupled receptor 12; Orphan receptor; Constitutive activation; Cryo-electron microscopy structure; cAMP
G protein-coupled receptor 12 (GPR12) plays a crucial role in thalamocortical functions and short-term memory. The cryo-electron microscopy structure of the GPR12-Gs complex reveals the key determinants for its high basal activity, including extracellular loop 2, TM1, TM7, TM6, and TM7.
G protein-coupled receptor 12 (GPR12) is an orphan G protein-coupled receptor that is highly expressed in the thalamus of the brain and plays a vital role in driving thalamocortical functions in short-term memory. GPR12 performs high constitutive activity and couples with Gs, increasing the intracellular cyc-lic adenosine monophosphate (cAMP) level when it is expressed. However, exploitation for drug devel-opment is limited since it is unclear how GPR12 initiates self-activation and signal transduction, and whether it can be modulated by endogenous or synthetic ligands. Here, we report the cryo-electron microscopy structure of the GPR12-Gs complex in the absence of agonists. Our structure reveals the key determinants for the intrinsically high basal activity of GPR12, including extracellular loop 2 partially occupying the orthosteric binding pocket, a tight-packed TM1 and TM7, and unique activation-related residues in TM6 and TM7. Together with mutagenesis data, this study will improve our understanding of the function and self-activation of the orphan receptor GPR12, enable the identification of endogenous ligands, and guide drug discovery efforts that target GPR12. (c) 2022 Science China Press. Published by Elsevier B.V.
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