4jjb - Revision history

OCA at 14:23, 8 November 2023

OCA — Wed, 08 Nov 2023 14:23:52 GMT

←Older revision		Revision as of 14:23, 8 November 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4jjb]] 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=4JJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JJB FirstGlance]. <br>		<table><tr><td colspan='2'>[[4jjb]] 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=4JJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JJB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 1.65Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=4jjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jjb OCA], [https://pdbe.org/4jjb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jjb RCSB], [https://www.ebi.ac.uk/pdbsum/4jjb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jjb 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=4jjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jjb OCA], [https://pdbe.org/4jjb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jjb RCSB], [https://www.ebi.ac.uk/pdbsum/4jjb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jjb ProSAT]</span></td></tr>
	</table>		</table>

OCA at 11:16, 24 November 2022

OCA — Thu, 24 Nov 2022 11:16:21 GMT

←Older revision		Revision as of 11:16, 24 November 2022
Line 1:		Line 1:

	==Crystal structure of the Abl-SH3 domain at pH3==		==Crystal structure of the Abl-SH3 domain at pH3==
-	<StructureSection load='4jjb' size='340' side='right' caption='[[4jjb]], [[Resolution\|resolution]] 1.65Å' scene=''>	+	<StructureSection load='4jjb' size='340' side='right'caption='[[4jjb]], [[Resolution\|resolution]] 1.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4jjb]] is a 1 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=4JJB OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4JJB FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4jjb]] 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=4JJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JJB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1abq\|1abq]], [[3eg0\|3eg0]], [[3eg2\|3eg2]], [[3egu\|3egu]], [[4jjc\|4jjc]], [[4jjd\|4jjd]]</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=4jjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jjb OCA], [https://pdbe.org/4jjb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jjb RCSB], [https://www.ebi.ac.uk/pdbsum/4jjb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jjb ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL, ABL1, JTK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4jjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jjb OCA], [~~http~~://pdbe.org/4jjb PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4jjb RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4jjb PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4jjb ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://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).	+	[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 ==		== Function ==
-	[~~[http~~://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>	+	[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 ==~~	+
-	The interaction of Abl-Src homology 3 domain (SH3) with the high affinity peptide p41 is the most notable example of the inconsistency existing between the currently accepted description of SH3 complexes and their binding thermodynamic signature. We had previously hypothesized that the presence of interfacial water molecules is partially responsible for this thermodynamic behavior. We present here a thermodynamic, structural, and molecular dynamics simulation study of the interaction of p41 with Abl-SH3 and a set of mutants designed to alter the water-mediated interaction network. Our results provide a detailed description of the dynamic properties of the interfacial water molecules and a molecular interpretation of the thermodynamic effects elicited by the mutations in terms of the modulation of the water-mediated hydrogen bond network. In the light of these results, a new dual binding mechanism is proposed that provides a better description of proline-rich ligand recognition by Abl-SH3 and that has important implications for rational design.	+

-	Role of interfacial water molecules in proline-rich ligand recognition by the Src homology 3 domain of Abl.,Palencia A, Camara-Artigas A, Pisabarro MT, Martinez JC, Luque I J Biol Chem. 2010 Jan 22;285(4):2823-33. Epub 2009 Nov 10. PMID:19906645<ref>PMID:19906645</ref>	+	==See Also==
-		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 4jjb" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Non-specific protein-tyrosine kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Camara-Artigas, A]]	+	[[Category: Camara-Artigas A]]
-	[[Category: Martin-Garcia~~, J M]]~~	+	[[Category: Martin-Garcia JM]]
-	~~[[Category: Beta shandwich]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Poly proline rich motif]]~~	+
-	~~[[Category: Sh3 domain]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 14:10, 15 November 2017

OCA — Wed, 15 Nov 2017 14:10:18 GMT

←Older revision		Revision as of 14:10, 15 November 2017
Line 23:		Line 23:
	</div>		</div>
	<div class="pdbe-citations 4jjb" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4jjb" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 14:53, 11 August 2016

OCA — Thu, 11 Aug 2016 14:53:17 GMT

←Older revision		Revision as of 14:53, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of the Abl-SH3 domain at pH3==		==Crystal structure of the Abl-SH3 domain at pH3==
	<StructureSection load='4jjb' size='340' side='right' caption='[[4jjb]], [[Resolution\|resolution]] 1.65Å' scene=''>		<StructureSection load='4jjb' size='340' side='right' caption='[[4jjb]], [[Resolution\|resolution]] 1.65Å' scene=''>
Line 7:		Line 8:
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL, ABL1, JTK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL, ABL1, JTK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4jjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jjb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jjb RCSB], [http://www.ebi.ac.uk/pdbsum/4jjb 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=4jjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jjb OCA], [http://pdbe.org/4jjb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jjb RCSB], [http://www.ebi.ac.uk/pdbsum/4jjb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jjb ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 15:		Line 16:
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	The ~~recognition~~ of ~~proline~~-~~rich ligands by~~ SH3 ~~domains~~ is ~~part~~ of the ~~process leading to diseases such as cancer or AIDS. Understanding~~ the ~~molecular determinants~~ of the ~~binding affinity and specificity~~ of ~~these interactions~~ is ~~crucial~~ for ~~the development of potent inhibitors with therapeutic potential~~. ~~In this~~ study~~, the crystallographic structure~~ of the ~~N114A mutant~~ of ~~the~~ SH3 ~~domain~~ of the ~~Abelson leukaemia virus tyrosine kinase complexed with a high~~-~~affinity peptide is presented~~. ~~The crystallization was carried out using~~ the ~~capillary counter-diffusion technique, which facilitates~~ the ~~screening, manipulation~~ and ~~transport~~ of the ~~crystals and allows~~ the ~~collection~~ of ~~X-ray data directly from~~ the ~~capillary in which the crystals were grown. The crystals~~ of the ~~N114A mutant belong to the orthorhombic P2(1)2(1)2(1) space group, with unit~~-~~cell parameters a = 48~~.~~2, b = 50.1, c = 56.4 A. The quality of~~ the ~~diffraction data set has allowed the structure~~ of ~~the complex to be determined at~~ a ~~resolution limit~~ of ~~1.75 A~~.	+	The interaction of Abl-Src homology 3 domain (SH3) with the high affinity peptide p41 is the most notable example of the inconsistency existing between the currently accepted description of SH3 complexes and their binding thermodynamic signature. We had previously hypothesized that the presence of interfacial water molecules is partially responsible for this thermodynamic behavior. We present here a thermodynamic, structural, and molecular dynamics simulation study of the interaction of p41 with Abl-SH3 and a set of mutants designed to alter the water-mediated interaction network. Our results provide a detailed description of the dynamic properties of the interfacial water molecules and a molecular interpretation of the thermodynamic effects elicited by the mutations in terms of the modulation of the water-mediated hydrogen bond network. In the light of these results, a new dual binding mechanism is proposed that provides a better description of proline-rich ligand recognition by Abl-SH3 and that has important implications for rational design.

-	~~Crystallization by capillary counter-diffusion and structure determination~~ of the ~~N114A mutant of the SH3~~ domain of Abl ~~tyrosine kinase complexed with a high-affinity peptide ligand~~.,Camara-Artigas A, ~~Palencia A~~, Martinez JC, Luque I~~, Gavira JA, Garcia-Ruiz JM Acta Crystallogr D~~ Biol ~~Crystallogr~~. ~~2007 May~~;63(~~Pt 5~~):~~646~~-52. Epub ~~2007, Apr 21~~. PMID:~~17452790~~<ref>PMID:~~17452790~~</ref>	+	Role of interfacial water molecules in proline-rich ligand recognition by the Src homology 3 domain of Abl.,Palencia A, Camara-Artigas A, Pisabarro MT, Martinez JC, Luque I J Biol Chem. 2010 Jan 22;285(4):2823-33. Epub 2009 Nov 10. PMID:19906645<ref>PMID:19906645</ref>

	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 4jjb" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 06:44, 22 January 2015

OCA — Thu, 22 Jan 2015 06:44:12 GMT

←Older revision		Revision as of 06:44, 22 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_4jjb\| PDB=4jjb \| SCENE= }}~~	+	==Crystal structure of the Abl-SH3 domain at pH3==
-	===Crystal structure of the Abl-SH3 domain at pH3===	+	<StructureSection load='4jjb' size='340' side='right' caption='[[4jjb]], [[Resolution\|resolution]] 1.65Å' scene=''>
-	~~{{ABSTRACT_PUBMED_17452790}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4jjb]] is a 1 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=4JJB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JJB FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1abq\|1abq]], [[3eg0\|3eg0]], [[3eg2\|3eg2]], [[3egu\|3egu]], [[4jjc\|4jjc]], [[4jjd\|4jjd]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ABL, ABL1, JTK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4jjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jjb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jjb RCSB], [http://www.ebi.ac.uk/pdbsum/4jjb PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
	[[http://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).		[[http://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 ==
		+	[[http://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 ==
		+	The recognition of proline-rich ligands by SH3 domains is part of the process leading to diseases such as cancer or AIDS. Understanding the molecular determinants of the binding affinity and specificity of these interactions is crucial for the development of potent inhibitors with therapeutic potential. In this study, the crystallographic structure of the N114A mutant of the SH3 domain of the Abelson leukaemia virus tyrosine kinase complexed with a high-affinity peptide is presented. The crystallization was carried out using the capillary counter-diffusion technique, which facilitates the screening, manipulation and transport of the crystals and allows the collection of X-ray data directly from the capillary in which the crystals were grown. The crystals of the N114A mutant belong to the orthorhombic P2(1)2(1)2(1) space group, with unit-cell parameters a = 48.2, b = 50.1, c = 56.4 A. The quality of the diffraction data set has allowed the structure of the complex to be determined at a resolution limit of 1.75 A.

-	~~==Function==~~	+	Crystallization by capillary counter-diffusion and structure determination of the N114A mutant of the SH3 domain of Abl tyrosine kinase complexed with a high-affinity peptide ligand.,Camara-Artigas A, Palencia A, Martinez JC, Luque I, Gavira JA, Garcia-Ruiz JM Acta Crystallogr D Biol Crystallogr. 2007 May;63(Pt 5):646-52. Epub 2007, Apr 21. PMID:17452790<ref>PMID:17452790</ref>
-	~~[[http://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>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4jjb]] is~~ a ~~1 chain structure~~. ~~Full crystallographic information is available from [http://oca~~.~~weizmann~~.~~ac.il~~/~~oca-bin/ocashort?id=4JJB OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:017452790</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Tyrosine kinase\|Tyrosine kinase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
-	[[Category: Camara-Artigas, A.]]	+	[[Category: Camara-Artigas, A]]
-	[[Category: Martin-Garcia, J M.]]	+	[[Category: Martin-Garcia, J M]]
	[[Category: Beta shandwich]]		[[Category: Beta shandwich]]
	[[Category: Kinase]]		[[Category: Kinase]]

OCA at 13:40, 12 March 2014

OCA — Wed, 12 Mar 2014 13:40:33 GMT

←Older revision		Revision as of 13:40, 12 March 2014
Line 1:		Line 1:
-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4jjb\| PDB=4jjb \| SCENE= }}
		+	===Crystal structure of the Abl-SH3 domain at pH3===
		+	{{ABSTRACT_PUBMED_17452790}}

-	~~The entry 4jjb~~ is ~~ON HOLD until Paper Publication~~	+	==Disease==
		+	[[http://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).

-	~~Authors~~: ~~Camara~~-~~Artigas~~, A., ~~Martin~~-~~Garcia~~, J.M.	+	==Function==
		+	[[http://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>

-	~~Description: Crystal~~ structure ~~of the Abl~~-~~SH3~~ domain ~~at pH3~~	+	==About this Structure==
		+	[[4jjb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JJB OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:017452790</ref><references group="xtra"/><references/>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Camara-Artigas, A.]]
		+	[[Category: Martin-Garcia, J M.]]
		+	[[Category: Beta shandwich]]
		+	[[Category: Kinase]]
		+	[[Category: Poly proline rich motif]]
		+	[[Category: Sh3 domain]]
		+	[[Category: Transferase]]

OCA at 14:55, 10 July 2013

OCA — Wed, 10 Jul 2013 14:55:38 GMT

←Older revision		Revision as of 14:55, 10 July 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4jjb is ON HOLD	+	The entry 4jjb is ON HOLD until Paper Publication

	Authors: Camara-Artigas, A., Martin-Garcia, J.M.		Authors: Camara-Artigas, A., Martin-Garcia, J.M.

	Description: Crystal structure of the Abl-SH3 domain at pH3		Description: Crystal structure of the Abl-SH3 domain at pH3

OCA: Protected "4jjb" [edit=sysop:move=sysop]

OCA — Wed, 13 Mar 2013 10:03:57 GMT

Protected "4jjb" [edit=sysop:move=sysop]

←Older revision

Revision as of 10:03, 13 March 2013

OCA: New page: '''Unreleased structure''' The entry 4jjb is ON HOLD Authors: Camara-Artigas, A., Martin-Garcia, J.M. Description: Crystal structure of the Abl-SH3 domain at pH3

OCA — Wed, 13 Mar 2013 10:03:56 GMT

New page: '''Unreleased structure''' The entry 4jjb is ON HOLD Authors: Camara-Artigas, A., Martin-Garcia, J.M. Description: Crystal structure of the Abl-SH3 domain at pH3

New page

'''Unreleased structure'''

The entry 4jjb is ON HOLD

Authors: Camara-Artigas, A., Martin-Garcia, J.M.

Description: Crystal structure of the Abl-SH3 domain at pH3