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Updated: Feb 12, 2026

Using In Vitro and In-cell SHAPE to Investigate Small Molecule Induced Pre-mRNA Structural Changes
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Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

Jianyun Huang1, Raja Dey1, Yufeng Wang1

  • 1Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, United States.

Journal of Molecular Biology
|March 26, 2018
PubMed

Insights

Small-molecule fascin inhibitors block cancer metastasis by distorting fascin protein's actin-binding sites. Structural analysis reveals how these inhibitors bind, offering insights into their mechanism of action for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Tumor metastasis causes most cancer deaths, with cell migration and invasion being key steps.
  • Filopodia, critical for tumor cell migration, rely on the actin-bundling protein fascin.
  • Small-molecule fascin inhibitors show potential in blocking cancer spread.

Purpose of the Study:

  • To elucidate the structural basis for the mechanism of action of small-molecule fascin inhibitors.
  • To understand how fascin inhibitors interact with the fascin protein at a molecular level.

Main Methods:

  • X-ray crystal structural analysis of fascin-inhibitor complexes.
  • Analysis of inhibitor-alone crystal structures to determine conformational dynamics.
  • Site-directed mutagenesis to assess the impact of specific residues on inhibitor sensitivity.

Main Results:

  • Fascin inhibitor binding induces a ~35° rotation of fascin domain 1, distorting actin-binding sites.
  • Small-molecule inhibitors exhibit dynamic conformations.
  • Mutations in inhibitor-interacting residues reduce fascin sensitivity to inhibitors.

Conclusions:

  • Structural insights reveal how fascin inhibitors disrupt fascin function.
  • Understanding this mechanism can guide the development of more effective anti-metastasis drugs.
  • This study provides a foundation for targeting fascin in cancer treatment.
Keywords:
actin cytoskeletoncrystal structurefascinsmall-molecule inhibitor

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