{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:21:06Z","timestamp":1785410466515,"version":"3.56.0"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,23]]},"abstract":"<jats:p>\n                    Lysophosphatidic acid receptor 5 (LPAR5) is a non-endothelial differentiation gene class A G protein\u2013coupled 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 G\n                    <jats:sub>q<\/jats:sub>\n                    at 2.96 \u00c5 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\u2013TM7, while the lipid tail inserts into a deep hydrophobic cavity formed by TM3\u2013TM5. Site-directed mutagenesis confirms the functional importance of these interactions. Remarkably, LPAR5 exhibits a noncanonical G protein coupling mode. Unlike previously reported GPCR\u2013G protein structures in which the G\u03b1 C-terminal \u03b15 helix (\u201cwavy hook\u201d) primarily engages TM6, the wavy hook in LPAR5 is positioned toward the intracellular loop 1\u2013helix 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\u2013G protein coupling and highlight the structural plasticity underlying signaling specificity in LPA receptors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2537482123","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T18:09:31Z","timestamp":1781806171000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Structural basis for lysophosphatidic acid recognition and atypical G\u03b1\n                    <sub>q<\/sub>\n                    coupling by LPAR5"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9689-0744","authenticated-orcid":false,"given":"Xin","family":"Li","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2620-448X","authenticated-orcid":false,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2142-6230","authenticated-orcid":false,"given":"Zhongliang","family":"Xing","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Hu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingning","family":"Yuan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6829-8144","authenticated-orcid":false,"given":"H. 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