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Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20

Author

Listed:
  • David Jonathan Wasilko

    (Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development)

  • Zachary Lee Johnson

    (Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development)

  • Mark Ammirati

    (Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development)

  • Ye Che

    (Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development)

  • Matthew C. Griffor

    (Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development)

  • Seungil Han

    (Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development)

  • Huixian Wu

    (Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development)

Abstract

Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. Despite the substantial progression of our structural understanding of GPCR activation by small molecule and peptide agonists, the molecular mechanism of GPCR activation by protein agonists remains unclear. Here, we present a 3.3-Å cryo-electron microscopy structure of the human chemokine receptor CCR6 bound to its endogenous ligand CCL20 and an engineered Go. CCL20 binds in a shallow extracellular pocket, making limited contact with the core 7-transmembrane (TM) bundle. The structure suggests that this mode of binding induces allosterically a rearrangement of a noncanonical toggle switch and the opening of the intracellular crevice for G protein coupling. Our results demonstrate that GPCR activation by a protein agonist does not always require substantial interactions between ligand and the 7TM core region.

Suggested Citation

  • David Jonathan Wasilko & Zachary Lee Johnson & Mark Ammirati & Ye Che & Matthew C. Griffor & Seungil Han & Huixian Wu, 2020. "Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16820-6
    DOI: 10.1038/s41467-020-16820-6
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    Cited by:

    1. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. David Jonathan Wasilko & Brian S. Gerstenberger & Kathleen A. Farley & Wei Li & Jennifer Alley & Mark E. Schnute & Ray J. Unwalla & Jorge Victorino & Kimberly K. Crouse & Ru Ding & Parag V. Sahasrabud, 2024. "Structural basis for CCR6 modulation by allosteric antagonists," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Jia Duan & Dan-Dan Shen & Tingting Zhao & Shimeng Guo & Xinheng He & Wanchao Yin & Peiyu Xu & Yujie Ji & Li-Nan Chen & Jinyu Liu & Huibing Zhang & Qiufeng Liu & Yi Shi & Xi Cheng & Hualiang Jiang & H., 2022. "Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Dawei Sun & Yonglian Sun & Eric Janezic & Tricia Zhou & Matthew Johnson & Caleigh Azumaya & Sigrid Noreng & Cecilia Chiu & Akiko Seki & Teresita L. Arenzana & John M. Nicoludis & Yongchang Shi & Baome, 2023. "Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Yann Waltenspühl & Janosch Ehrenmann & Santiago Vacca & Cristian Thom & Ohad Medalia & Andreas Plückthun, 2022. "Structural basis for the activation and ligand recognition of the human oxytocin receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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