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While HCAR2 activation, but not HCAR3 activation, is associated with side effects of cutaneous flushing, the structural features and ligand preferences of HCAR3 remain less understood. Here, we used Sf9 cells to express HCAR3-Gi and HCAR2-Gi complexes, and present cryo-EM structures of HCAR3-Gi complexes with agonists compound 6O (3.31 \u00c5), D-phenyllactic acid (3.05 \u00c5), IBC293 (3.26 \u00c5), and acifran (3.18\u00c5), as well as HCAR2-Gi complex with agonist acifran (2.72 \u00c5). Our findings reveal the mechanism behind 6O\u2019s highest affinity to HCAR3, attributed to its full occupation of both R1 and R2 regions of the orthosteric binding pocket. Moreover, combined with cAMP assay in HEK-293 cells, we have elucidated that the ligand selectivity between HCAR3 and HCAR2 depended on\n                    <jats:italic>\u03c0<\/jats:italic>\n                    \u2013\n                    <jats:italic>\u03c0<\/jats:italic>\n                    interaction with F107\n                    <jats:sup>3.32<\/jats:sup>\n                    (L107\n                    <jats:sup>3.32<\/jats:sup>\n                    in HCAR2) and ligand-binding pocket size difference, facilitated by key residues difference V\/L83\n                    <jats:sup>2.60<\/jats:sup>\n                    , Y\/N86\n                    <jats:sup>2.63<\/jats:sup>\n                    , and S\/W91\n                    <jats:sup>23.48<\/jats:sup>\n                    . Collectively, these structural insights lay the groundwork for developing HCAR3-specific drugs, potentially avoiding HCAR2-induced adverse effects.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003480","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T18:28:57Z","timestamp":1765218537000},"page":"e3003480","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structures of G-protein coupled receptor HCAR3 in complex with selective agonists reveal the basis for ligand recognition and selectivity"],"prefix":"10.1371","volume":"23","author":[{"given":"Fang","family":"Ye","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Binghao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaxi","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Miao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peiruo","family":"Ning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunlin","family":"Chi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhangsong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lezhi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningjie","family":"Gong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bangning","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhigang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chungen","family":"Qian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lizhe","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5115-0736","authenticated-orcid":true,"given":"Yang","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"issue":"2","key":"pbio.3003480.ref001","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1124\/pr.110.003301","article-title":"International Union of Basic and Clinical Pharmacology. 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