8aau - Revision history

OCA at 08:10, 7 February 2024

2024-02-07T08:10:39Z

←Older revision		Revision as of 08:10, 7 February 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[8aau]] 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=8AAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AAU FirstGlance]. <br>		<table><tr><td colspan='2'>[[8aau]] 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=8AAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AAU FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LH0:~{N}-[5-[2-[2,6-bis(chloranyl)phenyl]-5-[bis(fluoranyl)methyl]pyrazol-3-yl]-1,3-thiazol-2-yl]-2-methyl-propanamide'>LH0</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.74Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LH0:~{N}-[5-[2-[2,6-bis(chloranyl)phenyl]-5-[bis(fluoranyl)methyl]pyrazol-3-yl]-1,3-thiazol-2-yl]-2-methyl-propanamide'>LH0</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=8aau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aau OCA], [https://pdbe.org/8aau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aau RCSB], [https://www.ebi.ac.uk/pdbsum/8aau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aau 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=8aau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aau OCA], [https://pdbe.org/8aau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aau RCSB], [https://www.ebi.ac.uk/pdbsum/8aau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aau ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN] Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes.<ref>PMID:10196227</ref> <ref>PMID:10436159</ref> <ref>PMID:11832213</ref> <ref>PMID:12807904</ref> <ref>PMID:15660133</ref> <ref>PMID:16230460</ref> <ref>PMID:18028908</ref>		[https://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN] Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes.<ref>PMID:10196227</ref> <ref>PMID:10436159</ref> <ref>PMID:11832213</ref> <ref>PMID:12807904</ref> <ref>PMID:15660133</ref> <ref>PMID:16230460</ref> <ref>PMID:18028908</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 (LIMKi3; type I), 48 (TH470; type II), and 15 (TH257; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15. In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.
-
-	Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes.,Hanke T, Mathea S, Woortman J, Salah E, Berger BT, Tumber A, Kashima R, Hata A, Kuster B, Muller S, Knapp S J Med Chem. 2022 Oct 13;65(19):13264-13287. doi: 10.1021/acs.jmedchem.2c01106. , Epub 2022 Sep 22. PMID:36136092<ref>PMID:36136092</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 8aau" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:55, 22 February 2023

2023-02-22T12:55:21Z

←Older revision		Revision as of 12:55, 22 February 2023
Line 1:		Line 1:

	==LIM Domain Kinase 1 (LIMK1) bound to LIMKi3==		==LIM Domain Kinase 1 (LIMK1) bound to LIMKi3==
-	<StructureSection load='8aau' size='340' side='right'caption='[[8aau]]' scene=''>	+	<StructureSection load='8aau' size='340' side='right'caption='[[8aau]], [[Resolution\|resolution]] 1.74Å' 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=8AAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AAU FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[8aau]] 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=8AAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AAU 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=8aau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aau OCA], [https://pdbe.org/8aau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aau RCSB], [https://www.ebi.ac.uk/pdbsum/8aau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aau 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LH0:~{N}-[5-[2-[2,6-bis(chloranyl)phenyl]-5-[bis(fluoranyl)methyl]pyrazol-3-yl]-1,3-thiazol-2-yl]-2-methyl-propanamide'>LH0</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=8aau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aau OCA], [https://pdbe.org/8aau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aau RCSB], [https://www.ebi.ac.uk/pdbsum/8aau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aau ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN] Williams syndrome. Note=LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN] Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes.<ref>PMID:10196227</ref> <ref>PMID:10436159</ref> <ref>PMID:11832213</ref> <ref>PMID:12807904</ref> <ref>PMID:15660133</ref> <ref>PMID:16230460</ref> <ref>PMID:18028908</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	LIMKs are important regulators of actin and microtubule dynamics, and they play essential roles in many cellular processes. Deregulation of LIMKs has been linked to the development of diverse diseases, including cancers and cognitive disabilities, but well-characterized inhibitors known as chemical probes are still lacking. Here, we report the characterization of three highly selective LIMK1/2 inhibitors covering all canonical binding modes (type I/II/III) and the structure-based design of the type II/III inhibitors. Characterization of these chemical probes revealed a low nanomolar affinity for LIMK1/2, and all inhibitors 1 (LIMKi3; type I), 48 (TH470; type II), and 15 (TH257; type III) showed excellent selectivity in a comprehensive scanMAX kinase selectivity panel. Phosphoproteomics revealed remarkable differences between type I and type II inhibitors compared with the allosteric inhibitor 15. In phenotypic assays such as neurite outgrowth models of fragile X-chromosome, 15 showed promising activity, suggesting the potential application of allosteric LIMK inhibitors treating this orphan disease.
		+
		+	Development and Characterization of Type I, Type II, and Type III LIM-Kinase Chemical Probes.,Hanke T, Mathea S, Woortman J, Salah E, Berger BT, Tumber A, Kashima R, Hata A, Kuster B, Muller S, Knapp S J Med Chem. 2022 Oct 13;65(19):13264-13287. doi: 10.1021/acs.jmedchem.2c01106. , Epub 2022 Sep 22. PMID:36136092<ref>PMID:36136092</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 8aau" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Hanke T]]		[[Category: Hanke T]]

OCA at 05:03, 10 August 2022

2022-08-10T05:03:50Z

←Older revision		Revision as of 05:03, 10 August 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 8aau ~~is ON HOLD~~	+	==LIM Domain Kinase 1 (LIMK1) bound to LIMKi3==
-		+	<StructureSection load='8aau' size='340' side='right'caption='[[8aau]]' scene=''>
-	~~Authors~~: ~~Mathea~~, S., ~~Salah, E~~., ~~Hanke, T~~., ~~Knapp~~, S.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AAU FirstGlance]. <br>
-	~~Description: LIM Domain Kinase 1 (LIMK1) bound to LIMKi3~~	+	</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=8aau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aau OCA], [https://pdbe.org/8aau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aau RCSB], [https://www.ebi.ac.uk/pdbsum/8aau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aau ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Mathea, S~~]]	+	__TOC__
-	[[Category: Knapp, S]]	+	</StructureSection>
-	[[Category: ~~Hanke, T~~]]	+	[[Category: Large Structures]]
-	[[Category: Salah, E]]	+	[[Category: Hanke T]]
		+	[[Category: Knapp S]]
		+	[[Category: Mathea S]]
		+	[[Category: Salah E]]

OCA: Protected "8aau" [edit=sysop:move=sysop]

2022-07-13T04:07:52Z

Protected "8aau" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:07, 13 July 2022

OCA: New page: '''Unreleased structure''' The entry 8aau is ON HOLD Authors: Mathea, S., Salah, E., Hanke, T., Knapp, S. Description: LIM Domain Kinase 1 (LIMK1) bound to LIMKi3 [[Category: Unrelease...

2022-07-13T04:07:51Z

New page: '''Unreleased structure''' The entry 8aau is ON HOLD Authors: Mathea, S., Salah, E., Hanke, T., Knapp, S. Description: LIM Domain Kinase 1 (LIMK1) bound to LIMKi3 [[Category: Unrelease...

New page

'''Unreleased structure'''

The entry 8aau is ON HOLD

Authors: Mathea, S., Salah, E., Hanke, T., Knapp, S.

Description: LIM Domain Kinase 1 (LIMK1) bound to LIMKi3
[[Category: Unreleased Structures]]
[[Category: Mathea, S]]
[[Category: Knapp, S]]
[[Category: Hanke, T]]
[[Category: Salah, E]]