Structural basis for lysophosphatidylserine recognition by GPR34

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.

Structural insights into the agonist selectivity and structure-based engineering of the adenosine A3 receptor

“…Next, we inspected the interaction between A 3 R and G i . There are hallmark regions of the interactions between class A G i -coupling receptors, including A 3 R, and G i : ICL2 of a receptor as well as α5 of G i (Akasaka et al, 2022; Hua et al, 2020; Izume et al, 2024; Kato et al, 2019; Okamoto et al, 2021; Oshima et al, 2024; Sano et al, 2023; Yuan et al, 2021; Zhuang et al, 2022). In detail, around α5 of G i , several residues form hydrogen bonds, represented by the interaction between R108 3.50 and C351 H5.23 (superscript indicates the common Gα numbering [CGN] system(Flock et al, 2015)) (Figure 2F).…”

“…In detail, around α5 of G i , several residues form hydrogen bonds, represented by the interaction between R108 3.50 and C351 H5.23 (superscript indicates the common Gα numbering [CGN] system(Flock et al, 2015)) (Figure 2F). In the ICL2 of A 3 R, V116 34.51 penetrates into the hydrophobic cavity of G i , which is common in class A GPCRs(Akasaka et al, 2022; Hua et al, 2020; Iwama et al, 2023; Izume et al, 2024; Kato et al, 2019; Nagiri et al, 2021; Okamoto et al, 2021; Oshima et al, 2024; Rasmussen et al, 2011; Sano et al, 2023; Yuan et al, 2021; Zhuang et al, 2022) (Figure 2G). Furthermore, extensive ionic interactions are formed across ICL2.…”