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

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

doi:10.1016/j.jmb.2018.03.009

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

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

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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. Here 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. Our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.

Original language	English (US)
Pages (from-to)	1324-1335
Number of pages	12
Journal	Journal of Molecular Biology
Volume	430
Issue number	9
DOIs	https://doi.org/10.1016/j.jmb.2018.03.009
State	Published - Apr 27 2018

Bibliographical note

Funding Information:
We thank C. Shue, G. Wu, and J. Zhang for assistance with the project, and C. Hu, G. Wu, J. Zhang, and S. Zheng for comments on the structures and the manuscript. This work was supported by a Sponsored Research Agreement from Novita Pharmaceuticals to Weill Cornell Medical College and by a National Institutes of Health (NIH) grant CA193815. Part of this work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the NIGMS from the NIH (P41 GM103403). The Pilatus 6M detector on 24-ID-C beam line is funded by an NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Funding Information:
We thank C. Shue, G. Wu, and J. Zhang for assistance with the project, and C. Hu, G. Wu, J. Zhang, and S. Zheng for comments on the structures and the manuscript. This work was supported by a Sponsored Research Agreement from Novita Pharmaceuticals to Weill Cornell Medical College and by a National Institutes of Health (NIH) grant CA193815 . Part of this work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the NIGMS from the NIH ( P41 GM103403 ). The Pilatus 6M detector on 24-ID-C beam line is funded by an NIH-ORIP HEI grant ( S10 RR029205 ). This research used resources of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

actin cytoskeleton
crystal structure
fascin
small-molecule inhibitor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1016/j.jmb.2018.03.009

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916032

Find It

Find It at U of M Libraries

Cite this

@article{d38f0fa3b2cb4e7093a1b6209e3ed9be,

title = "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. Here 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. Our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.",

keywords = "actin cytoskeleton, crystal structure, fascin, small-molecule inhibitor",

author = "Jianyun Huang and Raja Dey and Yufeng Wang and Jean Jakoncic and Igor Kurinov and Huang, {Xin Yun}",

note = "Funding Information: We thank C. Shue, G. Wu, and J. Zhang for assistance with the project, and C. Hu, G. Wu, J. Zhang, and S. Zheng for comments on the structures and the manuscript. This work was supported by a Sponsored Research Agreement from Novita Pharmaceuticals to Weill Cornell Medical College and by a National Institutes of Health (NIH) grant CA193815. Part of this work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the NIGMS from the NIH (P41 GM103403). The Pilatus 6M detector on 24-ID-C beam line is funded by an NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Funding Information: We thank C. Shue, G. Wu, and J. Zhang for assistance with the project, and C. Hu, G. Wu, J. Zhang, and S. Zheng for comments on the structures and the manuscript. This work was supported by a Sponsored Research Agreement from Novita Pharmaceuticals to Weill Cornell Medical College and by a National Institutes of Health (NIH) grant CA193815 . Part of this work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the NIGMS from the NIH ( P41 GM103403 ). The Pilatus 6M detector on 24-ID-C beam line is funded by an NIH-ORIP HEI grant ( S10 RR029205 ). This research used resources of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = apr,

day = "27",

doi = "10.1016/j.jmb.2018.03.009",

language = "English (US)",

volume = "430",

pages = "1324--1335",

journal = "Journal of Molecular Biology",

issn = "0022-2836",

publisher = "Academic Press Inc.",

number = "9",

}

TY - JOUR

T1 - Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor

AU - Huang, Jianyun

AU - Dey, Raja

AU - Wang, Yufeng

AU - Jakoncic, Jean

AU - Kurinov, Igor

AU - Huang, Xin Yun

N1 - Funding Information: We thank C. Shue, G. Wu, and J. Zhang for assistance with the project, and C. Hu, G. Wu, J. Zhang, and S. Zheng for comments on the structures and the manuscript. This work was supported by a Sponsored Research Agreement from Novita Pharmaceuticals to Weill Cornell Medical College and by a National Institutes of Health (NIH) grant CA193815. Part of this work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the NIGMS from the NIH (P41 GM103403). The Pilatus 6M detector on 24-ID-C beam line is funded by an NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Funding Information: We thank C. Shue, G. Wu, and J. Zhang for assistance with the project, and C. Hu, G. Wu, J. Zhang, and S. Zheng for comments on the structures and the manuscript. This work was supported by a Sponsored Research Agreement from Novita Pharmaceuticals to Weill Cornell Medical College and by a National Institutes of Health (NIH) grant CA193815 . Part of this work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the NIGMS from the NIH ( P41 GM103403 ). The Pilatus 6M detector on 24-ID-C beam line is funded by an NIH-ORIP HEI grant ( S10 RR029205 ). This research used resources of the Advanced Photon Source, a US Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Publisher Copyright: © 2018 Elsevier Ltd

PY - 2018/4/27

Y1 - 2018/4/27

N2 - 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. Here 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. Our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.

AB - 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. Here 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. Our studies provide structural insights into the molecular mechanism of fascin protein function as well as the action of small-molecule fascin inhibitors.

KW - actin cytoskeleton

KW - crystal structure

KW - fascin

KW - small-molecule inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85044538804&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044538804&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2018.03.009

DO - 10.1016/j.jmb.2018.03.009

M3 - Article

C2 - 29573988

AN - SCOPUS:85044538804

SN - 0022-2836

VL - 430

SP - 1324

EP - 1335

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this