Structural insights into the G protein selectivity revealed by the human EP3-Gi signaling complex

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  • Suno, Ryoji
    Department of Medical Chemistry, Kansai Medical University
  • Sugita, Yukihiko
    Institute for Protein Research, Osaka University; Hakubi Center for Advanced Research, Kyoto University; Institute for Life and Medical Sciences, Kyoto University
  • Morimoto, Kazushi
    Physical Chemistry for Life Science Laboratory, Faculty of Pharmaceutical Sciences, Kyushu University
  • Takazaki, Hiroko
    Institute for Protein Research, Osaka University
  • Tsujimoto, Hirokazu
    Department of Cell Biology and Medical Chemistry, Graduate School of Medicine, Kyoto University
  • Hirose, Mika
    Institute for Protein Research, Osaka University
  • Suno-Ikeda, Chiyo
    Department of Medical Chemistry, Kansai Medical University
  • Nomura, Norimichi
    Department of Cell Biology and Medical Chemistry, Graduate School of Medicine, Kyoto University
  • Hino, Tomoya
    Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University; Center for Research on Green Sustainable Chemistry, Tottori University
  • Inoue, Asuka
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • Iwasaki, Kenji
    Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba
  • Kato, Takayuki
    Institute for Protein Research, Osaka University
  • Iwata, So
    Department of Cell Biology and Medical Chemistry, Graduate School of Medicine, Kyoto University
  • Kobayashi, Takuya
    Department of Medical Chemistry, Kansai Medical University; Japan Agency for Medical Research and Development (AMED), Core Research for Evolutional Science and Technology (CREST)

Description

Prostaglandin receptors have been implicated in a wide range of functions, including inflammation, immune response, reproduction, and cancer. Our group has previously determined the crystal structure of the active-like EP3 bound to its endogenous agonist, prostaglandin E₂. Here, we present the single-particle cryoelectron microscopy (cryo-EM) structure of the human EP3-Gi signaling complex at a resolution of 3.4 Å. The structure reveals the binding mode of Gi to EP3 and the structural changes induced in EP3 by Gi binding. In addition, we compare the structure of the EP3-Gi complex with other subtypes of prostaglandin receptors (EP2 and EP4) bound to Gs that have been previously reported and examine the differences in amino acid composition at the receptor-G protein interface. Mutational analysis reveals that the selectivity of the G protein depends on specific amino acid residues in the second intracellular loop and TM5.

Journal

  • Cell Reports

    Cell Reports 40 (11), 111323-, 2022-09

    Elsevier BV

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