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Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

Author

Listed:
  • Chong Wang

    (The Scripps Research Institute)

  • Huixian Wu

    (The Scripps Research Institute)

  • Tama Evron

    (Duke University Medical Center)

  • Eyal Vardy

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School)

  • Gye Won Han

    (The Scripps Research Institute)

  • Xi-Ping Huang

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School)

  • Sandy J. Hufeisen

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School)

  • Thomas J. Mangano

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School)

  • Dan J. Urban

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School)

  • Vsevolod Katritch

    (The Scripps Research Institute)

  • Vadim Cherezov

    (The Scripps Research Institute)

  • Marc G. Caron

    (Duke University Medical Center)

  • Bryan L. Roth

    (National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School)

  • Raymond C. Stevens

    (The Scripps Research Institute)

Abstract

The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6–2.8 Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D4736.54f elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.

Suggested Citation

  • Chong Wang & Huixian Wu & Tama Evron & Eyal Vardy & Gye Won Han & Xi-Ping Huang & Sandy J. Hufeisen & Thomas J. Mangano & Dan J. Urban & Vsevolod Katritch & Vadim Cherezov & Marc G. Caron & Bryan L. R, 2014. "Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5355
    DOI: 10.1038/ncomms5355
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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.

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