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Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation

Author

Listed:
  • Jiale Liang

    (Harbin Institute of Technology)

  • Asuka Inoue

    (Tohoku University)

  • Tatsuya Ikuta

    (Tohoku University)

  • Ruixue Xia

    (Harbin Institute of Technology)

  • Na Wang

    (Harbin Institute of Technology)

  • Kouki Kawakami

    (Tohoku University)

  • Zhenmei Xu

    (Harbin Institute of Technology)

  • Yu Qian

    (Harbin Institute of Technology)

  • Xinyan Zhu

    (Harbin Institute of Technology)

  • Anqi Zhang

    (Harbin Institute of Technology)

  • Changyou Guo

    (Harbin Institute of Technology)

  • Zhiwei Huang

    (Harbin Institute of Technology)

  • Yuanzheng He

    (Harbin Institute of Technology)

Abstract

Lysophosphatidylserine (LysoPS) is a lipid mediator that induces multiple cellular responses through binding to GPR174. Here, we present the cryo-electron microscopy (cryo-EM) structure of LysoPS-bound human GPR174 in complex with Gs protein. The structure reveals a ligand recognition mode, including the negatively charged head group of LysoPS forms extensive polar interactions with surrounding key residues of the ligand binding pocket, and the L-serine moiety buries deeply into a positive charged cavity in the pocket. In addition, the structure unveils a partially open pocket on transmembrane domain helix (TM) 4 and 5 for a lateral entry of ligand. Finally, the structure reveals a Gs engaging mode featured by a deep insertion of a helix 5 (αH5) and extensive polar interactions between receptor and αH5. Taken together, the information revealed by our structural study provides a framework for understanding LysoPS signaling and a rational basis for designing LysoPS receptor-targeting drugs.

Suggested Citation

  • Jiale Liang & Asuka Inoue & Tatsuya Ikuta & Ruixue Xia & Na Wang & Kouki Kawakami & Zhenmei Xu & Yu Qian & Xinyan Zhu & Anqi Zhang & Changyou Guo & Zhiwei Huang & Yuanzheng He, 2023. "Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36575-0
    DOI: 10.1038/s41467-023-36575-0
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    1. Yingying Nie & Zeming Qiu & Sijia Chen & Zhao Chen & Xiaocui Song & Yan Ma & Niu Huang & Jason G. Cyster & Sanduo Zheng, 2023. "Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Tamaki Izume & Ryo Kawahara & Akiharu Uwamizu & Luying Chen & Shun Yaginuma & Jumpei Omi & Hiroki Kawana & Fengjue Hou & Fumiya K. Sano & Tatsuki Tanaka & Kazuhiro Kobayashi & Hiroyuki H. Okamoto & Yo, 2024. "Structural basis for lysophosphatidylserine recognition by GPR34," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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