8u8f

GPR3 Orphan G-coupled Protein Receptor in complex with Dominant Negative Gs.

spinqualitylabelsall models 8u8f, resolution 3.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8u8f is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.49Å Ligands: PLM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The class A orphan G protein-coupled receptor (GPCR), GPR3, has been implicated in a variety of conditions, including Alzheimer's and premature ovarian failure. GPR3 constitutively couples with Galphas, resulting in the production of cAMP in cells. While tool compounds and several putative endogenous ligands have emerged for the receptor, its endogenous ligand, if it exists, remains a mystery. As novel potential drug targets, the structures of orphan GPCRs have been of increasing interest, revealing distinct modes of activation, including autoactivation, presence of constitutively activating mutations, or via cryptic ligands. Here, we present a cryo-electron microscopy (cryo-EM) structure of the orphan GPCR, GPR3 in complex with DNGalphas and Gbeta(1)gamma(2). The structure revealed clear density for a lipid-like ligand that bound within an extended hydrophobic groove, suggesting that the observed "constitutive activity" was likely due to activation via a lipid that may be ubiquitously present. Analysis of conformational variance within the cryo-EM data set revealed twisting motions of the GPR3 transmembrane helices that appeared coordinated with changes in the lipid-like density. We propose a mechanism for the binding of a lipid to its putative orthosteric binding pocket linked to the GPR3 dynamics. Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor, GPR3.,Russell IC, Zhang X, Bumbak F, McNeill SM, Josephs TM, Leeming MG, Christopoulos G, Venugopal H, Flocco MM, Sexton PM, Wootten D, Belousoff MJ Biochemistry. 2024 Mar 5;63(5):625-631. doi: 10.1021/acs.biochem.3c00647. Epub , 2024 Feb 20. PMID:38376112 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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