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6rd2

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ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2

Structural highlights

6rd2 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ENAH_HUMAN Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. ENAH induces the formation of F-actin rich outgrowths in fibroblasts. Acts synergistically with BAIAP2-alpha and downstream of NTN1 to promote filipodia formation (By similarity).^[1] ^[2]

Publication Abstract from PubMed

Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein-protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor ([Formula: see text] Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein-protein interaction involved in actin filament processing and cell migration.

Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells.,Barone M, Muller M, Chiha S, Ren J, Albat D, Soicke A, Dohmen S, Klein M, Bruns J, van Dinther M, Opitz R, Lindemann P, Beerbaum M, Motzny K, Roske Y, Schmieder P, Volkmer R, Nazare M, Heinemann U, Oschkinat H, Ten Dijke P, Schmalz HG, Kuhne R Proc Natl Acad Sci U S A. 2020 Nov 12. pii: 2007213117. doi:, 10.1073/pnas.2007213117. PMID:33184177^[3]

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

References

↑ Krugmann S, Jordens I, Gevaert K, Driessens M, Vandekerckhove J, Hall A. Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex. Curr Biol. 2001 Oct 30;11(21):1645-55. PMID:11696321
↑ Boeda B, Briggs DC, Higgins T, Garvalov BK, Fadden AJ, McDonald NQ, Way M. Tes, a specific Mena interacting partner, breaks the rules for EVH1 binding. Mol Cell. 2007 Dec 28;28(6):1071-82. PMID:18158903 doi:10.1016/j.molcel.2007.10.033
↑ Barone M, Muller M, Chiha S, Ren J, Albat D, Soicke A, Dohmen S, Klein M, Bruns J, van Dinther M, Opitz R, Lindemann P, Beerbaum M, Motzny K, Roske Y, Schmieder P, Volkmer R, Nazare M, Heinemann U, Oschkinat H, Ten Dijke P, Schmalz HG, Kuhne R. Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells. Proc Natl Acad Sci U S A. 2020 Nov 12. pii: 2007213117. doi:, 10.1073/pnas.2007213117. PMID:33184177 doi:http://dx.doi.org/10.1073/pnas.2007213117

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6rd2"

Categories: Homo sapiens | Large Structures | Synthetic construct | Barone M | Roske Y

@@ Line 3: / Line 3: @@
 <StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]], [[Resolution|resolution]] 1.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6rd2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RD2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6rd2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RD2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K1N:(3~{S},7~{R},10~{R},13~{S})-4-[(3~{S},6~{R},8~{a}~{S})-1-[(2~{S})-2-acetamido-3-(2-chlorophenyl)propanoyl]-5-oxidanylidene-spiro[1,2,3,8~{a}-tetrahydroindolizine-6,2-pyrrolidine]-3-yl]carbonyl-2-oxidanylidene-1,4-diazatricyclo[8.3.0.0^{3,7}]tridec-8-ene-13-carboxylic+acid'>K1N</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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]] 1&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NLW:L-LEUCINAMIDE'>NLW</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K1N:(3~{S},7~{R},10~{R},13~{S})-4-[(3~{S},6~{R},8~{a}~{S})-1-[(2~{S})-2-acetamido-3-(2-chlorophenyl)propanoyl]-5-oxidanylidene-spiro[1,2,3,8~{a}-tetrahydroindolizine-6,2-pyrrolidine]-3-yl]carbonyl-2-oxidanylidene-1,4-diazatricyclo[8.3.0.0^{3,7}]tridec-8-ene-13-carboxylic+acid'>K1N</scene>, <scene name='pdbligand=NLW:L-LEUCINAMIDE'>NLW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[5nd0|5nd0]], [[5nc2|5nc2]]</div></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ENAH, MENA ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6rd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rd2 OCA], [https://pdbe.org/6rd2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rd2 RCSB], [https://www.ebi.ac.uk/pdbsum/6rd2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rd2 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/ENAH_HUMAN ENAH_HUMAN]] Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. ENAH induces the formation of F-actin rich outgrowths in fibroblasts. Acts synergistically with BAIAP2-alpha and downstream of NTN1 to promote filipodia formation (By similarity).<ref>PMID:11696321</ref> <ref>PMID:18158903</ref>
+[https://www.uniprot.org/uniprot/ENAH_HUMAN ENAH_HUMAN] Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. ENAH induces the formation of F-actin rich outgrowths in fibroblasts. Acts synergistically with BAIAP2-alpha and downstream of NTN1 to promote filipodia formation (By similarity).<ref>PMID:11696321</ref> <ref>PMID:18158903</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Barone, M]]
+[[Category: Synthetic construct]]
-[[Category: Roske, Y]]
+[[Category: Barone M]]
-[[Category: Acta]]
+[[Category: Roske Y]]
-[[Category: Actin]]
-[[Category: Cell adhesion]]
-[[Category: Ena/vasp inhibitor]]
-[[Category: Proline-rich motif]]
-[[Category: Protein-protein interaction]]

6rd2

From Proteopedia

Current revision

ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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