Author:
Izume Tamaki,Kawahara Ryo,Uwamizu Akiharu,Chen Luying,Yaginuma Shun,Omi Jumpei,Kawana Hiroki,Sano Fumiya K.,Tanaka Tatsuki,Kobayashi Kazuhiro,Okamoto Hiroyuki H.,Kise Yoshiaki,Ohwada Tomohiko,Aoki Junken,Shihoya Wataru,Nureki Osamu
Abstract
AbstractGPR34 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-Gicomplex bound with either the LysoPS analogue S3E-LysoPS, which contains an ethoxy group at thesn-1 position, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. In both structures, 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, and the aromatic fatty acid surrogate of M1 forms stable hydrophobic interactions with the cavity, thus acting as a superagonist. 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, suggesting its short signal duration. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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