Structural basis for lysophosphatidylserine recognition by GPR34

Tamaki Izume, Ryo Kawahara, Akiharu Uwamizu, Luying Chen, Shun Yaginuma, Jumpei Omi, Hiroki Kawana, Fengjue Hou, Fumiya K. Sano, Tatsuki Tanaka, Kazuhiro Kobayashi, Hiroyuki H. Okamoto, Yoshiaki Kise, Tomohiko Ohwada (), Junken Aoki (), Wataru Shihoya () and Osamu Nureki ()
Additional contact information
Tamaki Izume: The University of Tokyo
Ryo Kawahara: The University of Tokyo
Akiharu Uwamizu: The University of Tokyo
Luying Chen: The University of Tokyo
Shun Yaginuma: The University of Tokyo
Jumpei Omi: The University of Tokyo
Hiroki Kawana: The University of Tokyo
Fengjue Hou: The University of Tokyo
Fumiya K. Sano: The University of Tokyo
Tatsuki Tanaka: The University of Tokyo
Kazuhiro Kobayashi: The University of Tokyo
Hiroyuki H. Okamoto: The University of Tokyo
Yoshiaki Kise: The University of Tokyo
Tomohiko Ohwada: The University of Tokyo
Junken Aoki: The University of Tokyo
Wataru Shihoya: The University of Tokyo
Osamu Nureki: The University of Tokyo

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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-Gi 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.

Date: 2024
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DOI: 10.1038/s41467-024-45046-z

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