6i16: Difference between revisions

Latest revision as of 11:44, 24 January 2024

CRYSTAL STRUCTURE OF FASCIN IN COMPLEX WITH COMPOUND 15

Structural highlights

6i16 is a 1 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 2Å
Ligands:	ACT, H0B
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

Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.

Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents.,Francis S, Croft D, Schuttelkopf AW, Parry C, Pugliese A, Cameron K, Claydon S, Drysdale M, Gardner C, Gohlke A, Goodwin G, Gray CH, Konczal J, McDonald L, Mezna M, Pannifer A, Paul NR, Machesky L, McKinnon H, Bower J Bioorg Med Chem Lett. 2019 Jan 30. pii: S0960-894X(19)30056-3. doi:, 10.1016/j.bmcl.2019.01.035. PMID:30773430^[5]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ Francis S, Croft D, Schuttelkopf AW, Parry C, Pugliese A, Cameron K, Claydon S, Drysdale M, Gardner C, Gohlke A, Goodwin G, Gray CH, Konczal J, McDonald L, Mezna M, Pannifer A, Paul NR, Machesky L, McKinnon H, Bower J. Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents. Bioorg Med Chem Lett. 2019 Jan 30. pii: S0960-894X(19)30056-3. doi:, 10.1016/j.bmcl.2019.01.035. PMID:30773430 doi:https://dx.doi.org/10.1016/j.bmcl.2019.01.035

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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] Francis S, Croft D, Schuttelkopf AW, Parry C, Pugliese A, Cameron K, Claydon S, Drysdale M, Gardner C, Gohlke A, Goodwin G, Gray CH, Konczal J, McDonald L, Mezna M, Pannifer A, Paul NR, Machesky L, McKinnon H, Bower J. Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents. Bioorg Med Chem Lett. 2019 Jan 30. pii: S0960-894X(19)30056-3. doi:, 10.1016/j.bmcl.2019.01.035. PMID:30773430 doi:https://dx.doi.org/10.1016/j.bmcl.2019.01.035

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[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
 ==CRYSTAL STRUCTURE OF FASCIN IN COMPLEX WITH COMPOUND 15==
-<StructureSection load='6i16' size='340' side='right' caption='[[6i16]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='6i16' size='340' side='right'caption='[[6i16]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6i16]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I16 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I16 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6i16]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I16 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I16 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H0B:6-[(3,4-dichlorophenyl)methyl]-~{N}-(1-methylpyrazol-4-yl)-5-oxidanylidene-1,6-naphthyridine-8-carboxamide'>H0B</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6i16 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i16 OCA], [http://pdbe.org/6i16 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i16 RCSB], [http://www.ebi.ac.uk/pdbsum/6i16 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i16 ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=H0B:6-[(3,4-dichlorophenyl)methyl]-~{N}-(1-methylpyrazol-4-yl)-5-oxidanylidene-1,6-naphthyridine-8-carboxamide'>H0B</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6i16 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i16 OCA], [https://pdbe.org/6i16 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i16 RCSB], [https://www.ebi.ac.uk/pdbsum/6i16 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i16 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/FSCN1_HUMAN 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.<ref>PMID:9362073</ref> <ref>PMID:9571235</ref> <ref>PMID:20137952</ref> <ref>PMID:20393565</ref>
+[https://www.uniprot.org/uniprot/FSCN1_HUMAN 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.<ref>PMID:9362073</ref> <ref>PMID:9571235</ref> <ref>PMID:20137952</ref> <ref>PMID:20393565</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 6i16" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Fascin|Fascin]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Schuettelkopf, A W]]
+[[Category: Homo sapiens]]
-[[Category: Actin bundling]]
+[[Category: Large Structures]]
-[[Category: Small molecule inhibition]]
+[[Category: Schuettelkopf AW]]
-[[Category: Structural protein]]

6i16: Difference between revisions

Latest revision as of 11:44, 24 January 2024

CRYSTAL STRUCTURE OF FASCIN IN COMPLEX WITH COMPOUND 15

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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