PDBsum entry 6li1

Membrane protein

PDB id: 6li1

Contents

Protein chain

441 a.a.

Ligands

OLC ×2

FMN

PEG

PGE

Waters ×7

PDB id:

6li1

Name:

Membrane protein

Title:

Crystal structure of gpr52 ligand free form with flavodoxin fusion

Structure:

Chimera of g-protein coupled receptor 52 and flavodoxin. Chain: a. Engineered: yes. Mutation: yes

Source:

Homo sapiens, desulfovibrio vulgaris str. Hildenborough. Human. Organism_taxid: 9606, 882. Strain: hildenborough. Gene: gpr52, dvu_2680. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.90Å R-factor: 0.245 R-free: 0.267

Authors:

Z.P.Luo,X.Lin,F.Xu,G.W.Han

Key ref:

X.Lin et al. (2020). Structural basis of ligand recognition and self-activation of orphan GPR52. Nature, 579, 152-157. PubMed id: 32076264

Date:

10-Dec-19 Release date: 26-Feb-20

Protein chain

P00323  (FLAV_DESVH) -  Flavodoxin from Nitratidesulfovibrio vulgaris (strain ATCC 29579 / DSM 644 / CCUG 34227 / NCIMB 8303 / VKM B-1760 / Hildenborough)

Seq: 148 a.a.

Struc: 441 a.a.*

Protein chain

Q9Y2T5  (GPR52_HUMAN) -  G-protein coupled receptor 52 from Homo sapiens

Seq: 361 a.a.

Struc: 441 a.a.*

* PDB and UniProt seqs differ at 146 residue positions (black crosses)

Nature 579:152-157 (2020)

PubMed id: 32076264

Structural basis of ligand recognition and self-activation of orphan GPR52.

X.Lin, M.Li, N.Wang, Y.Wu, Z.Luo, S.Guo, G.W.Han, S.Li, Y.Yue, X.Wei, X.Xie, Y.Chen, S.Zhao, J.Wu, M.Lei, F.Xu.

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^1,2. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G_s protein², but it is unclear how GPR52 and G_s 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_s-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 GPR52³. A fully active state is achieved when G_s 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.