7Y3G

Cryo-EM structure of a class A orphan GPCR

Summary for 7Y3G

• Entry DOI: 10.2210/pdb7y3g/pdb
• EMDB information: 33594
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: orphan g protein coupled-receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 150075.79

Authors

Liu, Z.J.,Hua, T.,Li, H.,Zhang, J.Y.,Luo, F. (deposition date: 2022-06-10, release date: 2023-06-07, Last modification date: 2024-11-06)

Primary citation

Li, H.,Zhang, J.,Yu, Y.,Luo, F.,Wu, L.,Liu, J.,Chen, N.,Liu, Z.,Hua, T.
Structural insight into the constitutive activity of human orphan receptor GPR12.
Sci Bull (Beijing), 68:95-104, 2023

PubMed 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 G, 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-G 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.

PubMed: 36593162
DOI: 10.1016/j.scib.2022.12.023

Experimental method

ELECTRON MICROSCOPY (2.77 Å)