Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias

• Maeda, Shintaro

  Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University; Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University

• Shiimura, Yuki

  Department of Cell Biology, Graduate School of Medicine, Kyoto University; Institute of Life Science, Kurume University

• Asada, Hidetsugu

  Department of Cell Biology, Graduate School of Medicine, Kyoto University

• Hirata, Kunio

  RIKEN SPring-8 Center

• Luo, Fangjia

  Department of Cell Biology, Graduate School of Medicine, Kyoto University; RIKEN SPring-8 Center

• Nango, Eriko

  Department of Cell Biology, Graduate School of Medicine, Kyoto University; RIKEN SPring-8 Center; Institute of Multidisciplinary Research for Advanced Materials, Tohoku University

• Tanaka, Nobuo

  Medical Research Support Center, Graduate School of Medicine, Kyoto University

• Toyomoto, Masayasu

  Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University

• Inoue, Asuka

  Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University

• Aoki, Junken

  Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University

• Iwata, So

  Department of Cell Biology, Graduate School of Medicine, Kyoto University; RIKEN SPring-8 Center

• Hagiwara, Masatoshi

  Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University; Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University; Medical Research Support Center, Graduate School of Medicine, Kyoto University; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University

Abstract

Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics.

Journal

• Science Advances

  Science Advances 7 (24), eabf5325-, 2021-06

  American Association for the Advancement of Science (AAAS)

Keywords

• Multidisciplinary

Details

• CRID: 1050569923250617216
• NII Article ID: 120007052733
• DOI: 10.1126/sciadv.abf5325
• HANDLE: 2433/263316
• ISSN: 23752548
• Web Site: https://syndication.highwire.org/content/doi/10.1126/sciadv.abf5325
• Web Site: https://www.science.org/doi/pdf/10.1126/sciadv.abf5325
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN