7w7x - Revision history

OCA at 17:37, 29 November 2023

OCA — Wed, 29 Nov 2023 17:37:33 GMT

←Older revision		Revision as of 17:37, 29 November 2023
Line 1:		Line 1:

	==The crystal structure of human abl1 kinase domain in complex with ABL1-A11==		==The crystal structure of human abl1 kinase domain in complex with ABL1-A11==
-	<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]]' scene=''>	+	<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]], [[Resolution\|resolution]] 2.00Å' 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=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7w7x]] is a 2 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=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X 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=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x ProSAT]</span></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]] 2.0000093Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8DW:5-[5-(dimethylcarbamoyl)pyridin-3-yl]-3-(5-fluorosulfonyloxy-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine'>8DW</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN] 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-153' 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. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.
		+
		+	Cell-Active, Reversible, and Irreversible Covalent Inhibitors that Selectively Target the Catalytic Lysine of BCR-ABL Kinase.,Chen P, Sun J, Zhu C, Tang G, Wang W, Xu M, Xiang M, Zhang C, Zhang ZM, Gao L, Yao SQ Angew Chem Int Ed Engl. 2022 Apr 19. doi: 10.1002/anie.202203878. PMID:35438229<ref>PMID:35438229</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7w7x" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]		*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Zhang ZM]]		[[Category: Zhang ZM]]
	[[Category: Zhu C]]		[[Category: Zhu C]]

OCA at 14:55, 31 August 2022

OCA — Wed, 31 Aug 2022 14:55:41 GMT

←Older revision		Revision as of 14:55, 31 August 2022
Line 1:		Line 1:

	==The crystal structure of human abl1 kinase domain in complex with ABL1-A11==		==The crystal structure of human abl1 kinase domain in complex with ABL1-A11==
-	<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]]~~, [[Resolution\|resolution]] 2.00Å~~' scene=''>	+	<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[7w7x]] is a 2 chain structure.~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8DW:5-[5-(dimethylcarbamoyl)pyridin-3-yl]-3-(5-fluorosulfonyloxy-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine'>8DW</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=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x ProSAT]</span></td></tr>
-	~~<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>~~	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x ProSAT]</span></td></tr>	+
	</table>		</table>
-	== Disease ==
-	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
-	== Function ==
-	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] 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-153' 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. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.
-
-	Cell-Active, Reversible, and Irreversible Covalent Inhibitors that Selectively Target the Catalytic Lysine of BCR-ABL Kinase.,Chen P, Sun J, Zhu C, Tang G, Wang W, Xu M, Xiang M, Zhang C, Zhang ZM, Gao L, Yao SQ Angew Chem Int Ed Engl. 2022 Apr 19. doi: 10.1002/anie.202203878. PMID:35438229<ref>PMID:35438229</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 7w7x" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]		*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific protein-tyrosine kinase]]~~	+	[[Category: Zhang ZM]]
-	[[Category: Zhang~~, Z M~~]]	+	[[Category: Zhu C]]
-	[[Category: Zhu, C]]	+
-	~~[[Category: Abl1]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:35, 29 June 2022

OCA — Wed, 29 Jun 2022 07:35:25 GMT

←Older revision		Revision as of 07:35, 29 June 2022
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 7w7x" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7w7x" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 06:37, 12 May 2022

OCA — Thu, 12 May 2022 06:37:49 GMT

←Older revision		Revision as of 06:37, 12 May 2022
Line 1:		Line 1:

	==The crystal structure of human abl1 kinase domain in complex with ABL1-A11==		==The crystal structure of human abl1 kinase domain in complex with ABL1-A11==
-	<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]]' scene=''>	+	<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]], [[Resolution\|resolution]] 2.00Å' 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=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7w7x]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X 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=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x 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=8DW:5-[5-(dimethylcarbamoyl)pyridin-3-yl]-3-(5-fluorosulfonyloxy-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine'>8DW</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] Note=A chromosomal aberration involving ABL1 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/ABL1_HUMAN ABL1_HUMAN]] 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-153' 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. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as ABL1 substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack ABL1 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1.<ref>PMID:9037071</ref> <ref>PMID:9144171</ref> <ref>PMID:9461559</ref> <ref>PMID:10391250</ref> <ref>PMID:12379650</ref> <ref>PMID:11971963</ref> <ref>PMID:12531427</ref> <ref>PMID:12672821</ref> <ref>PMID:15556646</ref> <ref>PMID:15031292</ref> <ref>PMID:15886098</ref> <ref>PMID:15657060</ref> <ref>PMID:16943190</ref> <ref>PMID:16678104</ref> <ref>PMID:17306540</ref> <ref>PMID:17623672</ref> <ref>PMID:18328268</ref> <ref>PMID:18945674</ref> <ref>PMID:19891780</ref> <ref>PMID:20417104</ref> <ref>PMID:16424036</ref> <ref>PMID:20357770</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.
		+
		+	Cell-Active, Reversible, and Irreversible Covalent Inhibitors that Selectively Target the Catalytic Lysine of BCR-ABL Kinase.,Chen P, Sun J, Zhu C, Tang G, Wang W, Xu M, Xiang M, Zhang C, Zhang ZM, Gao L, Yao SQ Angew Chem Int Ed Engl. 2022 Apr 19. doi: 10.1002/anie.202203878. PMID:35438229<ref>PMID:35438229</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7w7x" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Zhang ZM]]	+	[[Category: Non-specific protein-tyrosine kinase]]
-	[[Category: Zhu C]]	+	[[Category: Zhang, Z M]]
		+	[[Category: Zhu, C]]
		+	[[Category: Abl1]]
		+	[[Category: Transferase]]

OCA at 11:40, 27 April 2022

OCA — Wed, 27 Apr 2022 11:40:24 GMT

←Older revision		Revision as of 11:40, 27 April 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The ~~entry~~ 7w7x ~~is ON HOLD until Paper Publication~~	+	==The crystal structure of human abl1 kinase domain in complex with ABL1-A11==
-		+	<StructureSection load='7w7x' size='340' side='right'caption='[[7w7x]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7W7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7W7X FirstGlance]. <br>
-	~~Description~~:	+	</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=7w7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7w7x OCA], [https://pdbe.org/7w7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7w7x RCSB], [https://www.ebi.ac.uk/pdbsum/7w7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7w7x ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Zhang ZM]]
		+	[[Category: Zhu C]]

OCA at 08:43, 12 January 2022

OCA — Wed, 12 Jan 2022 08:43:50 GMT

←Older revision		Revision as of 08:43, 12 January 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7w7x is ON HOLD	+	The entry 7w7x is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7w7x" [edit=sysop:move=sysop]

OCA — Wed, 15 Dec 2021 15:49:27 GMT

Protected "7w7x" [edit=sysop:move=sysop]

←Older revision

Revision as of 15:49, 15 December 2021

OCA: New page: '''Unreleased structure''' The entry 7w7x is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 15 Dec 2021 15:49:26 GMT

New page: '''Unreleased structure''' The entry 7w7x is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7w7x is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]