6rd2 - Revision history

OCA at 11:51, 1 February 2024

OCA — Thu, 01 Feb 2024 11:51:39 GMT

←Older revision		Revision as of 11:51, 1 February 2024
Line 4:		Line 4:
	== Structural highlights ==		== 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>		<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=NLW:L-LEUCINAMIDE'>NLW</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]] 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>		<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>		</table>

OCA at 06:21, 26 October 2022

OCA — Wed, 26 Oct 2022 06:21:07 GMT

←Older revision		Revision as of 06:21, 26 October 2022
Line 3:		Line 3:
	<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]], [[Resolution\|resolution]] 1.00Å' scene=''>		<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]], [[Resolution\|resolution]] 1.00Å' scene=''>
	== Structural highlights ==		== 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='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='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~~='~~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>		<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>		</table>
	== Function ==		== 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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 22:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[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~~]]	+

OCA at 09:59, 24 February 2021

OCA — Wed, 24 Feb 2021 09:59:23 GMT

←Older revision		Revision as of 09:59, 24 February 2021
Line 1:		Line 1:

-	====	+	==ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2==
-	<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]]' scene=''>	+	<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]], [[Resolution\|resolution]] 1.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<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>
-	</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>	+	</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>
		+	<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='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>		</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>
		+	</div>
		+	<div class="pdbe-citations 6rd2" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Z-~~disk~~]]	+	[[Category: Barone, M]]
		+	[[Category: Roske, Y]]
		+	[[Category: Acta]]
		+	[[Category: Actin]]
		+	[[Category: Cell adhesion]]
		+	[[Category: Ena/vasp inhibitor]]
		+	[[Category: Proline-rich motif]]
		+	[[Category: Protein-protein interaction]]

OCA at 10:04, 17 February 2021

OCA — Wed, 17 Feb 2021 10:04:11 GMT

←Older revision		Revision as of 10:04, 17 February 2021
Line 1:		Line 1:

-	==~~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=''>	+	<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[6rd2]] is a 4 chain structure with sequence from [http://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 [~~http~~://proteopedia.org/fgij/fg.htm?mol=~~6RD2~~ FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= 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='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>
-	~~<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='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 ([http://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'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6rd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rd2 OCA], [~~http~~://pdbe.org/6rd2 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6rd2 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6rd2 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6rd2 ProSAT]</span></td></tr>	+
	</table>		</table>
-	== Function ==
-	[[http://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>
-	</div>
-	<div class="pdbe-citations 6rd2" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Barone, M]]~~	+	[[Category: Z-disk]]
-	~~[[Category: Roske, Y]]~~	+
-	~~[[Category: Acta]]~~	+
-	~~[[Category: Actin]]~~	+
-	~~[[Category: Cell adhesion]]~~	+
-	~~[[Category: Ena/vasp inhibitor]]~~	+
-	~~[[Category: Proline~~-~~rich motif]]~~	+
-	~~[[Category: Protein-protein interaction~~]]	+

OCA at 07:06, 25 November 2020

OCA — Wed, 25 Nov 2020 07:06:57 GMT

←Older revision		Revision as of 07:06, 25 November 2020
Line 1:		Line 1:

	==ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2==		==ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2==
-	<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]]' scene=''>	+	<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]], [[Resolution\|resolution]] 1.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>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 [http://proteopedia.org/fgij/fg.htm?mol=6RD2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6rd2]] is a 4 chain structure with sequence from [http://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 [http://proteopedia.org/fgij/fg.htm?mol=6RD2 FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rd2 OCA], [http://pdbe.org/6rd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rd2 RCSB], [http://www.ebi.ac.uk/pdbsum/6rd2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rd2 ProSAT]</span></td></tr>	+	</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>
		+	<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='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 ([http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6rd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rd2 OCA], [http://pdbe.org/6rd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rd2 RCSB], [http://www.ebi.ac.uk/pdbsum/6rd2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rd2 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://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>
		+	</div>
		+	<div class="pdbe-citations 6rd2" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Barone M]]	+	[[Category: Barone, M]]
-	[[Category: Roske Y]]	+	[[Category: Roske, Y]]
		+	[[Category: Acta]]
		+	[[Category: Actin]]
		+	[[Category: Cell adhesion]]
		+	[[Category: Ena/vasp inhibitor]]
		+	[[Category: Proline-rich motif]]
		+	[[Category: Protein-protein interaction]]

OCA at 05:28, 13 May 2020

OCA — Wed, 13 May 2020 05:28:34 GMT

←Older revision		Revision as of 05:28, 13 May 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 6rd2 is ON HOLD~~	+	==ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2==
-		+	<StructureSection load='6rd2' size='340' side='right'caption='[[6rd2]]' scene=''>
-	~~Authors: Barone, M., Roske, Y.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>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 [http://proteopedia.org/fgij/fg.htm?mol=6RD2 FirstGlance]. <br>
-	~~Description:~~ ENAH EVH1 in complex with Ac-[2-Cl-F]-[ProM-2]-[ProM-1]-TEDEL-NH2	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rd2 OCA], [http://pdbe.org/6rd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rd2 RCSB], [http://www.ebi.ac.uk/pdbsum/6rd2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rd2 ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Roske~~, Y]]	+	__TOC__
-	[[Category: Barone, M]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Barone M]]
		+	[[Category: Roske Y]]

OCA: Protected "6rd2" [edit=sysop:move=sysop]

OCA — Wed, 24 Apr 2019 05:09:42 GMT

Protected "6rd2" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:09, 24 April 2019

OCA: 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...

OCA — Wed, 24 Apr 2019 05:09:41 GMT

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...

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: Unreleased Structures]]
[[Category: Roske, Y]]
[[Category: Barone, M]]