{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:42:17Z","timestamp":1786948937831,"version":"build-2736575974"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"16","license":[{"start":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T00:00:00Z","timestamp":1649635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31971218"],"award-info":[{"award-number":["31971218"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32071197"],"award-info":[{"award-number":["32071197"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31971179"],"award-info":[{"award-number":["31971179"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,4,19]]},"abstract":"<jats:p>\n                    As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1 to S1PR5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or nonlipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its nonredundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here, we report four atomic resolution cryo-electron microscopy (cryo-EM) structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod [(S)-FTY720-P], or nonlipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step \u201cshallow to deep\u201d transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of G\n                    <jats:sub>\u03b1i<\/jats:sub>\n                    and further stabilize the complex by increasing the G\n                    <jats:sub>\u03b1i<\/jats:sub>\n                    interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1PRs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2117716119","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T05:53:06Z","timestamp":1649829186000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":63,"title":["Structural insights into sphingosine-1-phosphate receptor activation"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8698-6787","authenticated-orcid":false,"given":"Leiye","family":"Yu","sequence":"first","affiliation":[{"name":"Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China"},{"name":"Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200437, China"},{"name":"School of Life Sciences, University of Science and Technology of China, Anhui 230026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Licong","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2226-3165","authenticated-orcid":false,"given":"Bing","family":"Gan","sequence":"additional","affiliation":[{"name":"Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5169-8491","authenticated-orcid":false,"given":"Rujuan","family":"Ti","sequence":"additional","affiliation":[{"name":"Warshal Institute of Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingjie","family":"Xiao","sequence":"additional","affiliation":[{"name":"Zhangjiang Laboratory, National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yang","sequence":"additional","affiliation":[{"name":"Suzhou Connect Biopharmaceuticals, Ltd"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3658-272X","authenticated-orcid":false,"given":"Hongli","family":"Hu","sequence":"additional","affiliation":[{"name":"Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhe","family":"Zhu","sequence":"additional","affiliation":[{"name":"Warshal Institute of Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4176-8844","authenticated-orcid":false,"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4517-7216","authenticated-orcid":false,"given":"Ruobing","family":"Ren","sequence":"additional","affiliation":[{"name":"Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China"},{"name":"Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200437, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,4,11]]},"reference":[{"key":"e_1_3_5_1_2","first-page":"363","article-title":"Treatise on the chemical constitution of the brain: Based throughout upon original researches","volume":"22","author":"Anonymous","year":"1884","unstructured":"Anonymous, Treatise on the chemical constitution of the brain: Based throughout upon original researches. 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