8U8F
GPR3 Orphan G-coupled Protein Receptor in complex with Dominant Negative Gs.
Summary for 8U8F
| Entry DOI | 10.2210/pdb8u8f/pdb |
| EMDB information | 42023 |
| Descriptor | Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total) |
| Functional Keywords | gpr3, orphan gpcr, gpcr, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 131533.92 |
| Authors | Russell, I.C.,Belousoff, M.J.,Sexton, P. (deposition date: 2023-09-17, release date: 2024-03-06, Last modification date: 2025-05-21) |
| Primary citation | Russell, I.C.,Zhang, X.,Bumbak, F.,McNeill, S.M.,Josephs, T.M.,Leeming, M.G.,Christopoulos, G.,Venugopal, H.,Flocco, M.M.,Sexton, P.M.,Wootten, D.,Belousoff, M.J. Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor, GPR3. Biochemistry, 63:625-631, 2024 Cited by PubMed Abstract: 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 Gαs, 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 DNGαs and Gβγ. 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. PubMed: 38376112DOI: 10.1021/acs.biochem.3c00647 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.49 Å) |
Structure validation
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