8xbe | pdb_00008xbe

Human GPR34 -Gi complex bound to S3E-LysoPS

spinqualitylabelsall models 8xbe, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8xbe is a 5 chain structure with sequence from Bos taurus, Homo sapiens, Mus musculus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.4Å Ligands: KW0 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division. Publication Abstract from PubMed GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-G(i) complex bound with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. The ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster. The acyl chain of S3E-LysoPS is bent and fits into the L-shaped hydrophobic pocket in TM4-5 gap, and the aromatic fatty acid surrogate of M1 fits more appropriately. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34. Structural basis for lysophosphatidylserine recognition by GPR34.,Izume T, Kawahara R, Uwamizu A, Chen L, Yaginuma S, Omi J, Kawana H, Hou F, Sano FK, Tanaka T, Kobayashi K, Okamoto HH, Kise Y, Ohwada T, Aoki J, Shihoya W, Nureki O Nat Commun. 2024 Feb 7;15(1):902. doi: 10.1038/s41467-024-45046-z. PMID:38326347 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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