3kfa - Revision history

OCA at 08:14, 6 September 2023

2023-09-06T08:14:22Z

←Older revision		Revision as of 08:14, 6 September 2023
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	==Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template==		==Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template==
-	<StructureSection load='3kfa' size='340' side='right' caption='[[3kfa]], [[Resolution\|resolution]] 1.22Å' scene=''>	+	<StructureSection load='3kfa' size='340' side='right'caption='[[3kfa]], [[Resolution\|resolution]] 1.22Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3kfa]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Lk3_transgenic_mice Lk3 transgenic mice~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3KFA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3kfa]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KFA FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B91:3-{(E)-2-[6-(CYCLOPROPYLAMINO)-9H-PURIN-9-YL]ETHENYL}-4-METHYL-N-[3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE'>B91</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]] 1.22Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kf4\|3kf4]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B91:3-{(E)-2-[6-(CYCLOPROPYLAMINO)-9H-PURIN-9-YL]ETHENYL}-4-METHYL-N-[3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE'>B91</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Abl, Abl1, c-Abl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [https://pdbe.org/3kfa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [https://www.ebi.ac.uk/pdbsum/3kfa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kfa ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [~~http~~://pdbe.org/3kfa PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3kfa PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3kfa ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/ABL1_MOUSE ABL1_MOUSE]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks.<ref>PMID:8194526</ref> <ref>PMID:7780740</ref> <ref>PMID:9109492</ref> <ref>PMID:11279004</ref> <ref>PMID:11350980</ref> <ref>PMID:11279131</ref> <ref>PMID:12107171</ref> <ref>PMID:12748290</ref> <ref>PMID:14993293</ref> <ref>PMID:19903482</ref> <ref>PMID:19878872</ref>	+	[https://www.uniprot.org/uniprot/ABL1_MOUSE ABL1_MOUSE] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks.<ref>PMID:8194526</ref> <ref>PMID:7780740</ref> <ref>PMID:9109492</ref> <ref>PMID:11279004</ref> <ref>PMID:11350980</ref> <ref>PMID:11279131</ref> <ref>PMID:12107171</ref> <ref>PMID:12748290</ref> <ref>PMID:14993293</ref> <ref>PMID:19903482</ref> <ref>PMID:19878872</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kf/3kfa_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kf/3kfa_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
Line 31:		Line 29:
	</div>		</div>
	<div class="pdbe-citations 3kfa" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3kfa" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Lk3 transgenic mice~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Non-specific protein-tyrosine kinase~~]]	+	[[Category: Mus musculus]]
-	[[Category: Zhou, T]]	+	[[Category: Zhou T]]
-	~~[[Category: Abl]]~~	+
-	~~[[Category: Atp-binding]]~~	+
-	~~[[Category: Cml]]~~	+
-	~~[[Category: Drug resistance]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Nucleotide-binding]]~~	+
-	~~[[Category: Oncogene]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Tyrosine-protein kinase~~]]	+

OCA at 08:32, 1 November 2017

2017-11-01T08:32:56Z

←Older revision		Revision as of 08:32, 1 November 2017
Line 1:		Line 1:
		+
	==Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template==		==Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template==
	<StructureSection load='3kfa' size='340' side='right' caption='[[3kfa]], [[Resolution\|resolution]] 1.22Å' scene=''>		<StructureSection load='3kfa' size='340' side='right' caption='[[3kfa]], [[Resolution\|resolution]] 1.22Å' scene=''>
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	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Abl, Abl1, c-Abl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Abl, Abl1, c-Abl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [http://pdbe.org/3kfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [http://www.ebi.ac.uk/pdbsum/3kfa PDBsum]</span></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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [http://pdbe.org/3kfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [http://www.ebi.ac.uk/pdbsum/3kfa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3kfa ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 30:		Line 31:
	</div>		</div>
	<div class="pdbe-citations 3kfa" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3kfa" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 06:18, 8 February 2016

2016-02-08T06:18:40Z

←Older revision		Revision as of 06:18, 8 February 2016
Line 2:		Line 2:
	<StructureSection load='3kfa' size='340' side='right' caption='[[3kfa]], [[Resolution\|resolution]] 1.22Å' scene=''>		<StructureSection load='3kfa' size='340' side='right' caption='[[3kfa]], [[Resolution\|resolution]] 1.22Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3kfa]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Mus_musculus Mus musculus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KFA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3kfa]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KFA FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B91:3-{(E)-2-[6-(CYCLOPROPYLAMINO)-9H-PURIN-9-YL]ETHENYL}-4-METHYL-N-[3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE'>B91</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B91:3-{(E)-2-[6-(CYCLOPROPYLAMINO)-9H-PURIN-9-YL]ETHENYL}-4-METHYL-N-[3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE'>B91</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kf4\|3kf4]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kf4\|3kf4]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Abl, Abl1, c-Abl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 ~~Mus musculus~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Abl, Abl1, c-Abl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [http://www.ebi.ac.uk/pdbsum/3kfa PDBsum]</span></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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [http://pdbe.org/3kfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [http://www.ebi.ac.uk/pdbsum/3kfa PDBsum]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 19:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3kfa ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 29:		Line 29:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 3kfa" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 36:		Line 37:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Mus musculus~~]]	+	[[Category: Lk3 transgenic mice]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Zhou, T]]		[[Category: Zhou, T]]

OCA at 21:15, 24 December 2014

2014-12-24T21:15:18Z

←Older revision		Revision as of 21:15, 24 December 2014
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	<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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [http://www.ebi.ac.uk/pdbsum/3kfa PDBsum]</span></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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [http://www.ebi.ac.uk/pdbsum/3kfa PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ABL1_MOUSE ABL1_MOUSE]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks.<ref>PMID:8194526</ref> <ref>PMID:7780740</ref> <ref>PMID:9109492</ref> <ref>PMID:11279004</ref> <ref>PMID:11350980</ref> <ref>PMID:11279131</ref> <ref>PMID:12107171</ref> <ref>PMID:12748290</ref> <ref>PMID:14993293</ref> <ref>PMID:19903482</ref> <ref>PMID:19878872</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]

OCA at 17:04, 18 December 2014

2014-12-18T17:04:25Z

←Older revision		Revision as of 17:04, 18 December 2014
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-	~~{{STRUCTURE_3kfa\| PDB=3kfa \| SCENE= }}~~	+	==Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template==
-	===Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template===	+	<StructureSection load='3kfa' size='340' side='right' caption='[[3kfa]], [[Resolution\|resolution]] 1.22Å' scene=''>
-	{~~{ABSTRACT_PUBMED_19895503}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3kfa]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KFA FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B91:3-{(E)-2-[6-(CYCLOPROPYLAMINO)-9H-PURIN-9-YL]ETHENYL}-4-METHYL-N-[3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE'>B91</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kf4\|3kf4]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Abl, Abl1, c-Abl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></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=3kfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kfa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3kfa RCSB], [http://www.ebi.ac.uk/pdbsum/3kfa PDBsum]</span></td></tr>
		+	</table>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kf/3kfa_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we present crystal structures of Abl bound by two such inhibitors, based on a common N9-arenyl purine, and that represent both DFG-in and -out binding modes. In each structure the purine template is bound deeply in the adenine pocket and the novel vinyl linker forms a non-classical hydrogen bond to the gatekeeper residue, Thr315. Specific template substitutions promote either a DFG-in or -out binding mode, with the kinase binding site adjusting to optimize molecular recognition. Bcr-Abl T315I mutant kinase is resistant to all currently marketed Abl inhibitors, and is the focus of intense drug discovery efforts. Notably, our DFG-out inhibitor, AP24163, exhibits modest activity against this mutant, illustrating that this kinase mutant can be inhibited by DFG-out class inhibitors. Furthermore our DFG-out inhibitor exhibits dual Src-Abl activity, absent from the prototypical DFG-out inhibitor, imatinib as well as its analog, nilotinib. The data presented here provides structural guidance for the further design of novel potent DFG-out class inhibitors against Src, Abl and Abl T315I mutant kinases.

-	~~==Function==~~	+	Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.,Zhou T, Commodore L, Huang WS, Wang Y, Sawyer TK, Shakespeare WC, Clackson T, Zhu X, Dalgarno DC Chem Biol Drug Des. 2010 Jan;75(1):18-28. Epub 2009 Nov 5. PMID:19895503<ref>PMID:19895503</ref>
-	~~[[http://www.uniprot.org/uniprot/ABL1_MOUSE ABL1_MOUSE]] Non~~-~~receptor tyrosine~~-~~protein kinase that plays~~ a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. ~~Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1~~, ~~DBNL~~, ~~CTTN~~, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, ~~CRK~~, ~~CRKL~~, ~~DOK1~~, ~~EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR~~, ~~facilitates the formation of neuromuscular synapses through MUSK~~, ~~inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes~~. ~~Other substrates which are involved in endocytosis regulation are the caveolin~~ (~~CAV1~~) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-~~induced apoptosis~~. ~~Phosphorylates the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage~~. ~~Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks.<ref>~~PMID:8194526</ref> <ref>PMID:7780740</ref> <ref>PMID:9109492</ref> <ref>PMID:11279004</ref> <ref>PMID:11350980</ref> <ref>PMID:11279131</ref> <ref>PMID:12107171</ref> <ref>PMID:12748290</ref> <ref>PMID:14993293</ref> <ref>PMID:19903482</ref> <ref>PMID:~~19878872~~</ref>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[3kfa]] is~~ a ~~2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Mus_musculus Mus musculus]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:019895503</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Tyrosine kinase\|Tyrosine kinase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Mus musculus]]		[[Category: Mus musculus]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
-	[[Category: Zhou, T.]]	+	[[Category: Zhou, T]]
	[[Category: Abl]]		[[Category: Abl]]
	[[Category: Atp-binding]]		[[Category: Atp-binding]]

OCA: Protected "3kfa" [edit=sysop:move=sysop]

2013-04-04T02:12:59Z

Protected "3kfa" [edit=sysop:move=sysop]

←Older revision

Revision as of 02:12, 4 April 2013

OCA at 02:12, 4 April 2013

2013-04-04T02:12:44Z

←Older revision		Revision as of 02:12, 4 April 2013
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-	{{Seed}}
-	[[Image:3kfa.png\|left\|200px]]
-
-	<!--
-	The line below this paragraph, containing "STRUCTURE_3kfa", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_3kfa\| PDB=3kfa \| SCENE= }}		{{STRUCTURE_3kfa\| PDB=3kfa \| SCENE= }}
-
	===Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template===		===Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template===
		+	{{ABSTRACT_PUBMED_19895503}}

-		+	==Function==
-	<!--	+	[[http://www.uniprot.org/uniprot/ABL1_MOUSE ABL1_MOUSE]] Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, ABL1 regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks.<ref>PMID:8194526</ref> <ref>PMID:7780740</ref> <ref>PMID:9109492</ref> <ref>PMID:11279004</ref> <ref>PMID:11350980</ref> <ref>PMID:11279131</ref> <ref>PMID:12107171</ref> <ref>PMID:12748290</ref> <ref>PMID:14993293</ref> <ref>PMID:19903482</ref> <ref>PMID:19878872</ref>
-	~~The line below this paragraph~~, ~~{{ABSTRACT_PUBMED_19895503}}~~, ~~adds~~ the ~~Publication Abstract to~~ the ~~page~~	+
-	(as ~~it appears on PubMed at http://www~~.~~pubmed~~.~~gov~~), where ~~19895503~~ is the ~~PubMed ID number~~.	+
-	-->	+
-	~~{{ABSTRACT_PUBMED_19895503}}~~	+

	==About this Structure==		==About this Structure==
-	~~3KFA~~ is a 2 ~~chains~~ structure with ~~sequences~~ from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA].	+	[[3kfa]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA].

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~19895503~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:019895503</ref><references group="xtra"/><references/>
	[[Category: Mus musculus]]		[[Category: Mus musculus]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
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	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Tyrosine-protein kinase]]		[[Category: Tyrosine-protein kinase]]
-
-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Sep 1 09:18:55 2010''

OCA at 05:10, 1 September 2010

2010-09-01T05:10:48Z

←Older revision		Revision as of 05:10, 1 September 2010
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	{{Seed}}		{{Seed}}
-	[[Image:3kfa.~~jpg~~\|left\|200px]]	+	[[Image:3kfa.png\|left\|200px]]

	<!--		<!--
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	==About this Structure==		==About this Structure==
-	3KFA is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/~~Abelson_murine_leukemia_virus Abelson murine leukemia virus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA].	+	3KFA is a 2 chains structure with sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA].

	==Reference==		==Reference==
	<ref group="xtra">PMID:19895503</ref><references group="xtra"/>		<ref group="xtra">PMID:19895503</ref><references group="xtra"/>
-	[[Category: ~~Abelson murine leukemia virus~~]]	+	[[Category: Mus musculus]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Zhou, T.]]		[[Category: Zhou, T.]]
Line 35:		Line 35:
	[[Category: Nucleotide-binding]]		[[Category: Nucleotide-binding]]
	[[Category: Oncogene]]		[[Category: Oncogene]]
		+	[[Category: Transferase]]
	[[Category: Tyrosine-protein kinase]]		[[Category: Tyrosine-protein kinase]]

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on ~~Thu Dec 24 07~~:33:~~58 2009~~''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Sep 1 09:18:55 2010''

OCA at 05:33, 24 December 2009

2009-12-24T05:33:59Z

←Older revision		Revision as of 05:33, 24 December 2009
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	===Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template===		===Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template===

		+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_19895503}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 19895503 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_19895503}}

	==About this Structure==		==About this Structure==
Line 31:		Line 37:
	[[Category: Tyrosine-protein kinase]]		[[Category: Tyrosine-protein kinase]]

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on ~~Wed~~ Dec ~~23 09~~:50:11 2009''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Dec 24 07:33:58 2009''

OCA at 07:50, 23 December 2009

2009-12-23T07:50:12Z

←Older revision		Revision as of 07:50, 23 December 2009
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-	~~'''Unreleased structure'''~~	+	{{Seed}}
		+	[[Image:3kfa.jpg\|left\|200px]]

-	The ~~entry 3kfa~~ is ~~ON HOLD~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3kfa", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_3kfa\| PDB=3kfa \| SCENE= }}

-	~~Authors: Zhou, T.~~	+	===Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template===

-	Description: Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed ~~Nov 18 18~~:54:40 2009''	+	==About this Structure==
		+	3KFA is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Abelson_murine_leukemia_virus Abelson murine leukemia virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KFA OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:19895503</ref><references group="xtra"/>
		+	[[Category: Abelson murine leukemia virus]]
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Zhou, T.]]
		+	[[Category: Abl]]
		+	[[Category: Atp-binding]]
		+	[[Category: Cml]]
		+	[[Category: Drug resistance]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Nucleotide-binding]]
		+	[[Category: Oncogene]]
		+	[[Category: Tyrosine-protein kinase]]
		+
		+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Dec 23 09:50:11 2009''