8XBH

Human GPR34 -Gi complex bound to M1

Summary for 8XBH

• Entry DOI: 10.2210/pdb8xbh/pdb
• EMDB information: 38218
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, 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, ... (6 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 159819.17

Authors

Kawahara, R.,Shihoya, W.,Nureki, O. (deposition date: 2023-12-06, release date: 2023-12-27, Last modification date: 2024-10-30)

Primary citation

Izume, T.,Kawahara, R.,Uwamizu, A.,Chen, L.,Yaginuma, S.,Omi, J.,Kawana, H.,Hou, F.,Sano, F.K.,Tanaka, T.,Kobayashi, K.,Okamoto, H.H.,Kise, Y.,Ohwada, T.,Aoki, J.,Shihoya, W.,Nureki, O.
Structural basis for lysophosphatidylserine recognition by GPR34.
Nat Commun, 15:902-902, 2024

PubMed Abstract: 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 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.

PubMed: 38326347
DOI: 10.1038/s41467-024-45046-z

Experimental method

ELECTRON MICROSCOPY (2.83 Å)