Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

Huang, Jianyun; Dey, Raja; Wang, Yufeng; Jakoncic, Jean; Kurinov, Igor; Huang, Xin-Yun

doi:10.1016/j.jmb.2018.03.009

Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

Journal Article · Wed Mar 21 00:00:00 EDT 2018 · Journal of Molecular Biology

DOI:https://doi.org/10.1016/j.jmb.2018.03.009· OSTI ID:1466640

Huang, Jianyun ^[1]; Dey, Raja ^[1]; Wang, Yufeng ^[1]; Jakoncic, Jean ^[2]; Kurinov, Igor ^[3]; Huang, Xin-Yun ^[1]

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

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 ~ 35^o 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.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Lab. (BNL), Upton, NY (United States); Weill Cornell Medical College of Cornell Univ., New York, NY (United States)

Sponsoring Organization:: National Inst. of Health (NIH) (United States); Novita Pharmaceuticals (United States); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 1466640

Alternate ID(s):: OSTI ID: 1452846

Report Number(s):: BNL--207925-2018-JAAM

Journal Information:: Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 9 Vol. 430; ISSN 0022-2836

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
actin cytoskeleton
crystal structure
fascin
small-molecule inhibitor

Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

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