6rd2
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 6rd2 is ON HOLD Authors: Barone, M., Roske, Y. Description: ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2 [[Category: Unrelease...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2== | |
| + | <StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]], [[Resolution|resolution]] 1.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1Å</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='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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:33184177</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 6rd2" style="background-color:#fffaf0;"></div> |
| - | [[Category: Barone | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Synthetic construct]] | ||
| + | [[Category: Barone M]] | ||
| + | [[Category: Roske Y]] | ||
Current revision
ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2
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