6li2
Crystal structure of GPR52 ligand free form with rubredoxin fusion
Structural highlights
FunctionGPR52_HUMAN Gs-coupled receptor activated by antipsychotics reserpine leading to an increase in intracellular cAMP and its internalization (PubMed:24587241). May play a role in locomotor activity through modulation of dopamine, NMDA and ADORA2A-induced locomotor activity. These behavioral changes are accompanied by modulation of the dopamine receptor signaling pathway in striatum (PubMed:24587241). Modulates HTT level via cAMP-dependent but PKA independent mechanisms throught activation of RAB39B that translocates HTT to the endoplasmic reticulum, thus avoiding proteasome degradation (PubMed:25738228).[1] [2] RUBR_CLOPA Rubredoxin is a small nonheme, iron protein lacking acid-labile sulfide. Its single Fe, chelated to 4 Cys, functions as an electron acceptor and may also stabilize the conformation of the molecule. Publication Abstract from PubMedGPR52 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 Gs protein(2), but it is unclear how GPR52 and Gs 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 Gs-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(3). A fully active state is achieved when Gs 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. Structural basis of ligand recognition and self-activation of orphan GPR52.,Lin X, Li M, Wang N, Wu Y, Luo Z, Guo S, Han GW, Li S, Yue Y, Wei X, Xie X, Chen Y, Zhao S, Wu J, Lei M, Xu F Nature. 2020 Feb 19. pii: 10.1038/s41586-020-2019-0. doi:, 10.1038/s41586-020-2019-0. PMID:32076264[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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