Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor
Abstract
Tumor metastasis is responsible for ~ 90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main actin-bundling protein in filopodia. Small-molecule fascin inhibitors block tumor cell migration, invasion, and metastasis. In this paper, we present the structural basis for the mechanism of action of these small-molecule fascin inhibitors. X-ray crystal structural analysis of a complex of fascin and a fascin inhibitor shows that binding of the fascin inhibitor to the hydrophobic cleft between the domains 1 and 2 of fascin induces a ~ 35o rotation of domain 1, leading to the distortion of both the actin-binding sites 1 and 2 on fascin. Furthermore, the crystal structures of an inhibitor alone indicate that the conformations of the small-molecule inhibitors are dynamic. Mutations of the inhibitor-interacting residues decrease the sensitivity of fascin to the inhibitors. Finally, our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.
- Authors:
-
- Weill Cornell Medical College of Cornell Univ., New York, NY (United States). Dept. of Physiology and Biophysics
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
- Cornell Univ., Lemont, IL (United States). NE-CAT. Dept. of Chemistry and Chemical Biology
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States); Weill Cornell Medical College of Cornell Univ., New York, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); Novita Pharmaceuticals (United States)
- OSTI Identifier:
- 1466640
- Report Number(s):
- BNL-207925-2018-JAAM
Journal ID: ISSN 0022-2836
- Grant/Contract Number:
- SC0012704; AC02-06CH11357; CA193815; P41 GM103403; S10 RR029205
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Molecular Biology
- Additional Journal Information:
- Journal Volume: 430; Journal Issue: 9; Journal ID: ISSN 0022-2836
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; crystal structure; fascin; actin cytoskeleton; small-molecule inhibitor
Citation Formats
Huang, Jianyun, Dey, Raja, Wang, Yufeng, Jakoncic, Jean, Kurinov, Igor, and Huang, Xin-Yun. Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor. United States: N. p., 2018.
Web. doi:10.1016/j.jmb.2018.03.009.
Huang, Jianyun, Dey, Raja, Wang, Yufeng, Jakoncic, Jean, Kurinov, Igor, & Huang, Xin-Yun. Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor. United States. https://doi.org/10.1016/j.jmb.2018.03.009
Huang, Jianyun, Dey, Raja, Wang, Yufeng, Jakoncic, Jean, Kurinov, Igor, and Huang, Xin-Yun. Wed .
"Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor". United States. https://doi.org/10.1016/j.jmb.2018.03.009. https://www.osti.gov/servlets/purl/1466640.
@article{osti_1466640,
title = {Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor},
author = {Huang, Jianyun and Dey, Raja and Wang, Yufeng and Jakoncic, Jean and Kurinov, Igor and Huang, Xin-Yun},
abstractNote = {Tumor metastasis is responsible for ~ 90% of all cancer deaths. One of the key steps of tumor metastasis is tumor cell migration and invasion. Filopodia are cell surface extensions that are critical for tumor cell migration. Fascin protein is the main actin-bundling protein in filopodia. Small-molecule fascin inhibitors block tumor cell migration, invasion, and metastasis. In this paper, we present the structural basis for the mechanism of action of these small-molecule fascin inhibitors. X-ray crystal structural analysis of a complex of fascin and a fascin inhibitor shows that binding of the fascin inhibitor to the hydrophobic cleft between the domains 1 and 2 of fascin induces a ~ 35o rotation of domain 1, leading to the distortion of both the actin-binding sites 1 and 2 on fascin. Furthermore, the crystal structures of an inhibitor alone indicate that the conformations of the small-molecule inhibitors are dynamic. Mutations of the inhibitor-interacting residues decrease the sensitivity of fascin to the inhibitors. Finally, our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.},
doi = {10.1016/j.jmb.2018.03.009},
journal = {Journal of Molecular Biology},
number = 9,
volume = 430,
place = {United States},
year = {Wed Mar 21 00:00:00 EDT 2018},
month = {Wed Mar 21 00:00:00 EDT 2018}
}
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Works referencing / citing this record:
Novel anti-invasive properties of a Fascin1 inhibitor on colorectal cancer cells
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