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Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs

Chong Wang1, Huixian Wu1, Tama Evron2

  • 1Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Nature Communications
|July 11, 2014
PubMed

Insights

Structural insights into the Smoothened receptor (SMO) reveal how mutations cause chemoresistance. Understanding these interactions is key for developing effective hedgehog pathway cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The Smoothened receptor (SMO) is crucial for hedgehog pathway signaling, which plays a role in development and cancer.
  • SMO antagonists show promise in cancer treatment, but resistance mutations can limit their efficacy.

Purpose of the Study:

  • To elucidate the structural basis of SMO modulation by small molecules.
  • To understand the mechanisms underlying chemoresistance in SMO-targeted therapies.

Main Methods:

  • X-ray crystallography was used to determine the structures of human SMO bound to ligands.
  • Structures were resolved at 2.6-2.8 Å resolution.

Main Results:

  • Three crystal structures of human SMO with antagonists (SANT1, Anta XV) and an agonist (SAG1.5) were determined.
  • SANT1 binds to a deeper site within the SMO transmembrane domain compared to other ligands.
  • Specific interactions at D473 explain how chemoresistance mutations affect SMO antagonist binding.
  • The agonist SAG1.5 induces conformational changes in the SMO binding pocket, suggesting a mechanism for activation.

Conclusions:

  • The study reveals the structural basis for SMO modulation by small molecules, including antagonists and agonists.
  • Understanding these structures provides a foundation for designing more effective SMO-targeting drugs and overcoming resistance mechanisms.

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