6LI3

cryo-EM structure of GPR52-miniGs-NB35

Summary for 6LI3

• Entry DOI: 10.2210/pdb6li3/pdb
• Related: 6LI2
• EMDB information: 0902
• Descriptor: G-protein coupled receptor 52, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (5 entities in total)
• Functional Keywords: g-protein coupled receptor, orphan gpcr, self-activation, cryo-em, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 129352.70

Authors

Li, M.,Wang, N.,Xu, F.,Wu, J.,Lei, M. (deposition date: 2019-12-10, release date: 2020-02-26, Last modification date: 2024-11-13)

Primary citation

Lin, X.,Li, M.,Wang, N.,Wu, Y.,Luo, Z.,Guo, S.,Han, G.W.,Li, S.,Yue, Y.,Wei, X.,Xie, X.,Chen, Y.,Zhao, S.,Wu, J.,Lei, M.,Xu, F.
Structural basis of ligand recognition and self-activation of orphan GPR52.
Nature, 579:152-157, 2020

PubMed Abstract: GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G protein, but it is unclear how GPR52 and G couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52. A fully active state is achieved when G is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.

PubMed: 32076264
DOI: 10.1038/s41586-020-2019-0

Experimental method

ELECTRON MICROSCOPY (3.32 Å)