6LI0

Crystal structure of GPR52 in complex with agonist c17

Summary for 6LI0

• Entry DOI: 10.2210/pdb6li0/pdb
• Descriptor: Chimera of G-protein coupled receptor 52 and Flavodoxin, N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1-[2-[[3-(trifluoromethyl)phenyl]methyl]-1-benzothiophen-7-yl]pyrazole-4-carboxamide, FLAVIN MONONUCLEOTIDE, ... (7 entities in total)
• Functional Keywords: human gpr52 receptor, class a, orphan gpcr, membrane protein, agonist c17, flavodoxin, lcp
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 60648.52

Authors

Luo, Z.P.,Lin, X.,Xu, F.,Han, G.W. (deposition date: 2019-12-10, release date: 2020-02-26, Last modification date: 2024-10-23)

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

X-RAY DIFFRACTION (2.2 Å)