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Crystal structure of the Frizzled 4 receptor in a ligand-free state

Author

Listed:
  • Shifan Yang

    (iHuman Institute, ShanghaiTech University)

  • Yiran Wu

    (iHuman Institute, ShanghaiTech University)

  • Ting-Hai Xu

    (Innovation and Integration Program, Van Andel Research Institute)

  • Parker W. Waal

    (Innovation and Integration Program, Van Andel Research Institute)

  • Yuanzheng He

    (Harbin Institute of Technology)

  • Mengchen Pu

    (iHuman Institute, ShanghaiTech University)

  • Yuxiang Chen

    (iHuman Institute, ShanghaiTech University
    ShanghaiTech University
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zachary J. DeBruine

    (Innovation and Integration Program, Van Andel Research Institute)

  • Bingjie Zhang

    (iHuman Institute, ShanghaiTech University)

  • Saheem A. Zaidi

    (University of Southern California)

  • Petr Popov

    (University of Southern California
    Moscow Institute of Physics and Technology)

  • Yu Guo

    (iHuman Institute, ShanghaiTech University
    ShanghaiTech University
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Gye Won Han

    (University of Southern California)

  • Yang Lu

    (Harbin Institute of Technology)

  • Kelly Suino-Powell

    (Innovation and Integration Program, Van Andel Research Institute)

  • Shaowei Dong

    (iHuman Institute, ShanghaiTech University
    ShanghaiTech University
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Kaleeckal G. Harikumar

    (Mayo Clinic)

  • Laurence J. Miller

    (Mayo Clinic)

  • Vsevolod Katritch

    (University of Southern California
    Moscow Institute of Physics and Technology)

  • H. Eric Xu

    (Innovation and Integration Program, Van Andel Research Institute
    Chinese Academy of Sciences)

  • Wenqing Shui

    (iHuman Institute, ShanghaiTech University
    ShanghaiTech University)

  • Raymond C. Stevens

    (iHuman Institute, ShanghaiTech University
    ShanghaiTech University)

  • Karsten Melcher

    (Innovation and Integration Program, Van Andel Research Institute)

  • Suwen Zhao

    (iHuman Institute, ShanghaiTech University
    ShanghaiTech University)

  • Fei Xu

    (iHuman Institute, ShanghaiTech University
    ShanghaiTech University)

Abstract

Frizzled receptors (FZDs) are class-F G-protein-coupled receptors (GPCRs) that function in Wnt signalling and are essential for developing and adult organisms1,2. As central mediators in this complex signalling pathway, FZDs serve as gatekeeping proteins both for drug intervention and for the development of probes in basic and in therapeutic research. Here we present an atomic-resolution structure of the human Frizzled 4 receptor (FZD4) transmembrane domain in the absence of a bound ligand. The structure reveals an unusual transmembrane architecture in which helix VI is short and tightly packed, and is distinct from all other GPCR structures reported so far. Within this unique transmembrane fold is an extremely narrow and highly hydrophilic pocket that is not amenable to the binding of traditional GPCR ligands. We show that such a pocket is conserved across all FZDs, which may explain the long-standing difficulties in the development of ligands for these receptors. Molecular dynamics simulations on the microsecond timescale and mutational analysis uncovered two coupled, dynamic kinks located at helix VII that are involved in FZD4 activation. The stability of the structure in its ligand-free form, an unfavourable pocket for ligand binding and the two unusual kinks on helix VII suggest that FZDs may have evolved a novel ligand-recognition and activation mechanism that is distinct from that of other GPCRs.

Suggested Citation

  • Shifan Yang & Yiran Wu & Ting-Hai Xu & Parker W. Waal & Yuanzheng He & Mengchen Pu & Yuxiang Chen & Zachary J. DeBruine & Bingjie Zhang & Saheem A. Zaidi & Petr Popov & Yu Guo & Gye Won Han & Yang Lu , 2018. "Crystal structure of the Frizzled 4 receptor in a ligand-free state," Nature, Nature, vol. 560(7720), pages 666-670, August.
  • Handle: RePEc:nat:nature:v:560:y:2018:i:7720:d:10.1038_s41586-018-0447-x
    DOI: 10.1038/s41586-018-0447-x
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    Citations

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    Cited by:

    1. James Hillier & Yuguang Zhao & Loic Carrique & Tomas Malinauskas & Reinis R. Ruza & Tao-Hsin Chang & Gangshun Yi & Helen M. E. Duyvesteyn & Jing Yu & Weixian Lu & Els Pardon & Jan Steyaert & Yanan Zhu, 2024. "Structural insights into Frizzled3 through nanobody modulators," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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