Authors
Xin Li, Kai Wang, Zhongliang Xing, Min Zhang, Wen Hu, Qingning Yuan, H Eric Xu, Li-Hua Zhao
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 25. Pages e2537482123. Jun 23, 2026. Epub Jun 18, 2026.
Abstract
Lysophosphatidic acid receptor 5 (LPAR5) is a non-endothelial differentiation gene class A G protein-coupled receptor that regulates neuropathic pain, itch, and cancer progression through coupling to G proteins. Here, we report the cryo-EM structure of LPAR5 bound to 1-oleoyl-lysophosphatidic acid (LPA) in complex with Gq at 2.96 Å resolution, revealing a distinct mode of receptor activation and G protein coupling. The phosphate headgroup of LPA forms extensive polar interactions with residues from extracellular loop 2 and transmembrane helices TM5-TM7, while the lipid tail inserts into a deep hydrophobic cavity formed by TM3-TM5. Site-directed mutagenesis confirms the functional importance of these interactions. Remarkably, LPAR5 exhibits a noncanonical G protein coupling mode. Unlike previously reported GPCR-G protein structures in which the Gα C-terminal α5 helix ("wavy hook") primarily engages TM6, the wavy hook in LPAR5 is positioned toward the intracellular loop 1-helix 8 interface. This configuration is associated with limited TM6 outward displacement and modest rearrangement at the toggle-switch position (6.48). The resulting interface is stabilized by receptor-specific interactions and supported by functional data. Together, these findings reveal an alternative mode of GPCR-G protein coupling and highlight the structural plasticity underlying signaling specificity in LPA receptors.
PMID:
42313925
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.
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