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Structure of the human smoothened receptor bound to an antitumour agent

Author

Listed:
  • Chong Wang

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Huixian Wu

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Vsevolod Katritch

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Gye Won Han

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Xi-Ping Huang

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA)

  • Wei Liu

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Fai Yiu Siu

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Bryan L. Roth

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA)

  • Vadim Cherezov

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Raymond C. Stevens

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

Abstract

The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.

Suggested Citation

  • Chong Wang & Huixian Wu & Vsevolod Katritch & Gye Won Han & Xi-Ping Huang & Wei Liu & Fai Yiu Siu & Bryan L. Roth & Vadim Cherezov & Raymond C. Stevens, 2013. "Structure of the human smoothened receptor bound to an antitumour agent," Nature, Nature, vol. 497(7449), pages 338-343, May.
    • Handle: RePEc:nat:nature:v:497:y:2013:i:7449:d:10.1038_nature12167
    DOI: 10.1038/nature12167
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    Cited by:

    1. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, 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.

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