6b0t

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

Structural highlights

6b0t is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.8Å
Ligands:C7V
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FSCN1_HUMAN Organizes filamentous actin into bundles with a minimum of 4.1:1 actin/fascin ratio. Plays a role in the organization of actin filament bundles and the formation of microspikes, membrane ruffles, and stress fibers. Important for the formation of a diverse set of cell protrusions, such as filopodia, and for cell motility and migration.[1] [2] [3] [4]

Publication Abstract from PubMed

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.

Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor.,Huang J, Dey R, Wang Y, Jakoncic J, Kurinov I, Huang XY J Mol Biol. 2018 Mar 21. pii: S0022-2836(18)30137-2. doi:, 10.1016/j.jmb.2018.03.009. PMID:29573988[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Adams JC. Characterization of cell-matrix adhesion requirements for the formation of fascin microspikes. Mol Biol Cell. 1997 Nov;8(11):2345-63. PMID:9362073
  2. ↑ Yamashiro S, Yamakita Y, Ono S, Matsumura F. Fascin, an actin-bundling protein, induces membrane protrusions and increases cell motility of epithelial cells. Mol Biol Cell. 1998 May;9(5):993-1006. PMID:9571235
  3. ↑ Li A, Dawson JC, Forero-Vargas M, Spence HJ, Yu X, Konig I, Anderson K, Machesky LM. The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion. Curr Biol. 2010 Feb 23;20(4):339-45. doi: 10.1016/j.cub.2009.12.035. Epub 2010, Feb 4. PMID:20137952 doi:10.1016/j.cub.2009.12.035
  4. ↑ Chen L, Yang S, Jakoncic J, Zhang JJ, Huang XY. Migrastatin analogues target fascin to block tumour metastasis. Nature. 2010 Apr 15;464(7291):1062-6. PMID:20393565 doi:10.1038/nature08978
  5. ↑ Huang J, Dey R, Wang Y, Jakoncic J, Kurinov I, Huang XY. Structural Insights into the Induced-fit Inhibition of Fascin by a Small-Molecule Inhibitor. J Mol Biol. 2018 Mar 21. pii: S0022-2836(18)30137-2. doi:, 10.1016/j.jmb.2018.03.009. PMID:29573988 doi:http://dx.doi.org/10.1016/j.jmb.2018.03.009

Contents


PDB ID 6b0t

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