EMD-33594

Single-particle
2.77 Å
EMD-33594 Deposition: 10/06/2022
Map released: 07/06/2023
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-33594

Cryo-EM structure of a class A orphan GPCR

EMD-33594

Single-particle
2.77 Å
EMD-33594 Deposition: 10/06/2022
Map released: 07/06/2023
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Lama glama
Sample: Complex of GPCR and G protein
Fitted models: 7y3g (Avg. Q-score: 0.486)

Deposition Authors: Liu ZJ, Hua T, Li H , Zhang JY, Luo F
Structural insight into the constitutive activity of human orphan receptor GPR12.
Li H , Zhang J, Yu Y, Luo F , Wu L, Liu J, Chen N , Liu Z, Hua T
(2023) Sci Bull (Beijing) , 68 , 95 - 104
PUBMED: 36593162
DOI: doi:10.1016/j.scib.2022.12.023
ISSN: 2095-9281
Abstract:
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 cyclic adenosine monophosphate (cAMP) level when it is expressed. However, exploitation for drug development 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.