4k9e - Revision history

OCA at 11:47, 30 November 2022

2022-11-30T11:47:03Z

←Older revision		Revision as of 11:47, 30 November 2022
Line 1:		Line 1:

	==Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D==		==Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D==
-	<StructureSection load='4k9e' size='340' side='right' caption='[[4k9e]], [[Resolution\|resolution]] 2.70Å' scene=''>	+	<StructureSection load='4k9e' size='340' side='right'caption='[[4k9e]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4k9e]] is a 3 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~] and [~~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=4K9E OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4K9E FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4k9e]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K9E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K9E FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4k94\|4k94]]</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=4k9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k9e OCA], [https://pdbe.org/4k9e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k9e RCSB], [https://www.ebi.ac.uk/pdbsum/4k9e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k9e ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KIT, SCFR ([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/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4k9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k9e OCA], [~~http~~://pdbe.org/4k9e PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4k9e RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4k9e PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4k9e ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Defects in KIT are a cause of piebald trait (PBT) [MIM:[~~http~~://omim.org/entry/172800 172800]]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref> Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[~~http~~://omim.org/entry/606764 606764]].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref> Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[~~http~~://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref> Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[~~http~~://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>	+	[https://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN] Defects in KIT are a cause of piebald trait (PBT) [MIM:[https://omim.org/entry/172800 172800]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref> Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[https://omim.org/entry/606764 606764].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref> Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[https://omim.org/entry/273300 273300]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref> Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref>	+	[https://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 4k9e" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4k9e" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Lk3 transgenic mice~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Receptor protein-tyrosine kinase~~]]	+	[[Category: Mus musculus]]
-	[[Category: Boggon~~, T J~~]]	+	[[Category: Boggon TJ]]
-	[[Category: Lax, I]]	+	[[Category: Lax I]]
-	[[Category: Resheynyak~~, A V~~]]	+	[[Category: Resheynyak AV]]
-	[[Category: Schlessinger, J]]	+	[[Category: Schlessinger J]]
-	~~[[Category: Fab]]~~	+
-	~~[[Category: Igg]]~~	+
-	~~[[Category: Immune system~~]]	+

OCA at 17:44, 11 August 2016

2016-08-11T17:44:24Z

←Older revision		Revision as of 17:44, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D==		==Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D==
	<StructureSection load='4k9e' size='340' side='right' caption='[[4k9e]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='4k9e' size='340' side='right' caption='[[4k9e]], [[Resolution\|resolution]] 2.70Å' scene=''>
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	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KIT, SCFR ([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">KIT, SCFR ([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/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4k9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k9e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4k9e RCSB], [http://www.ebi.ac.uk/pdbsum/4k9e 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=4k9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k9e OCA], [http://pdbe.org/4k9e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4k9e RCSB], [http://www.ebi.ac.uk/pdbsum/4k9e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4k9e ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
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	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 4k9e" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:20, 4 January 2015

2015-01-04T12:20:17Z

←Older revision		Revision as of 12:20, 4 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_4k9e\| PDB=4k9e \| SCENE= }}~~	+	==Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D==
-	===Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D===	+	<StructureSection load='4k9e' size='340' side='right' caption='[[4k9e]], [[Resolution\|resolution]] 2.70Å' scene=''>
-	~~{{ABSTRACT_PUBMED_24127596}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4k9e]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [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=4K9E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K9E FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4k94\|4k94]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KIT, SCFR ([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/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4k9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k9e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4k9e RCSB], [http://www.ebi.ac.uk/pdbsum/4k9e PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
	[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Defects in KIT are a cause of piebald trait (PBT) [MIM:[http://omim.org/entry/172800 172800]]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref> Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[http://omim.org/entry/606764 606764]].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref> Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref> Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[http://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>		[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Defects in KIT are a cause of piebald trait (PBT) [MIM:[http://omim.org/entry/172800 172800]]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref> Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[http://omim.org/entry/606764 606764]].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref> Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref> Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[http://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>
-		+	== Function ==
-	==Function==	+
	[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref>		[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Somatic oncogenic mutations in the receptor tyrosine kinase KIT function as major drivers of gastrointestinal stromal tumors and a subset of acute myeloid leukemia, melanoma, and other cancers. Although treatment of these cancers with tyrosine kinase inhibitors shows dramatic responses and durable disease control, drug resistance followed by clinical progression of disease eventually occurs in virtually all patients. In this report, we describe inhibitory KIT antibodies that bind to the membrane-proximal Ig-like D4 of KIT with significant overlap with an epitope in D4 that mediates homotypic interactions essential for KIT activation. Crystal structures of the anti-KIT antibody in complex with KIT D4 and D5 allowed design of affinity-matured libraries that were used to isolate variants with increased affinity and efficacy. Isolated antibodies showed KIT inhibition together with suppression of cell proliferation driven by ligand-stimulated WT or constitutively activated oncogenic KIT mutant. These antibodies represent a unique therapeutic approach and a step toward the development of "naked" or toxin-conjugated KIT antibodies for the treatment of KIT-driven cancers.

-	~~==About this Structure==~~	+	Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region.,Reshetnyak AV, Nelson B, Shi X, Boggon TJ, Pavlenco A, Mandel-Bausch EM, Tome F, Suzuki Y, Sidhu SS, Lax I, Schlessinger J Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17832-7. doi:, 10.1073/pnas.1317118110. Epub 2013 Oct 14. PMID:24127596<ref>PMID:24127596</ref>
-	~~[[4k9e]] is a 3 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Human Human] and [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=4K9E OCA].~~	+

-	==~~Reference~~==	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~<ref group="xtra">PMID:024127596</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	</div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Human]]		[[Category: Human]]
	[[Category: Lk3 transgenic mice]]		[[Category: Lk3 transgenic mice]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Boggon, T J.]]	+	[[Category: Boggon, T J]]
-	[[Category: Lax, I.]]	+	[[Category: Lax, I]]
-	[[Category: Resheynyak, A V.]]	+	[[Category: Resheynyak, A V]]
-	[[Category: Schlessinger, J.]]	+	[[Category: Schlessinger, J]]
	[[Category: Fab]]		[[Category: Fab]]
	[[Category: Igg]]		[[Category: Igg]]
	[[Category: Immune system]]		[[Category: Immune system]]

OCA at 13:39, 12 March 2014

2014-03-12T13:39:53Z

←Older revision		Revision as of 13:39, 12 March 2014
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	{{STRUCTURE_4k9e\| PDB=4k9e \| SCENE= }}		{{STRUCTURE_4k9e\| PDB=4k9e \| SCENE= }}
	===Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D===		===Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D===
		+	{{ABSTRACT_PUBMED_24127596}}

	==Disease==		==Disease==
Line 9:		Line 10:

	==About this Structure==		==About this Structure==
-	[[4k9e]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~] and [http://en.wikipedia.org/wiki/~~Mus_musculus Mus musculus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K9E OCA].	+	[[4k9e]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [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=4K9E OCA].

	==Reference==		==Reference==
-	<references group="xtra"/><references/>	+	<ref group="xtra">PMID:024127596</ref><references group="xtra"/><references/>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
-	[[Category: ~~Mus musculus~~]]	+	[[Category: Lk3 transgenic mice]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Boggon, T J.]]		[[Category: Boggon, T J.]]

OCA at 08:08, 16 October 2013

2013-10-16T08:08:53Z

←Older revision		Revision as of 08:08, 16 October 2013
Line 1:		Line 1:
-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4k9e\| PDB=4k9e \| SCENE= }}
		+	===Crystal structure of KIT D4D5 fragment in complex with anti-Kit antibodies Fab79D===

-	~~The~~ entry ~~4k9e~~ is ~~ON HOLD~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Defects in KIT are a cause of piebald trait (PBT) [MIM:[http://omim.org/entry/172800 172800]]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref> Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[http://omim.org/entry/606764 606764]].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref> Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref> Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[http://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>

-	~~Authors~~: ~~Resheynyak~~, A.V., ~~Boggon~~, T.J., ~~Lax~~, I., ~~Schlessinger~~, J.	+	==Function==
		+	[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref>

-	~~Description~~: ~~Structural basis for KIT receptor inhibition by antibodies targeting the D4 membrane proximal region~~	+	==About this Structure==
		+	[[4k9e]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K9E OCA].
		+
		+	==Reference==
		+	<references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Mus musculus]]
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Boggon, T J.]]
		+	[[Category: Lax, I.]]
		+	[[Category: Resheynyak, A V.]]
		+	[[Category: Schlessinger, J.]]
		+	[[Category: Fab]]
		+	[[Category: Igg]]
		+	[[Category: Immune system]]

OCA at 07:19, 8 May 2013

2013-05-08T07:19:02Z

←Older revision		Revision as of 07:19, 8 May 2013
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	The entry 4k9e is ON HOLD		The entry 4k9e is ON HOLD

-	Authors: Resheynyak, A.V., Boggon T.J., Lax I., Schlessinger J.	+	Authors: Resheynyak, A.V., Boggon, T.J., Lax, I., Schlessinger, J.

	Description: Structural basis for KIT receptor inhibition by antibodies targeting the D4 membrane proximal region		Description: Structural basis for KIT receptor inhibition by antibodies targeting the D4 membrane proximal region

OCA: Protected "4k9e" [edit=sysop:move=sysop]

2013-05-02T07:13:02Z

Protected "4k9e" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:13, 2 May 2013

OCA: New page: '''Unreleased structure''' The entry 4k9e is ON HOLD Authors: Resheynyak, A.V., Boggon T.J., Lax I., Schlessinger J. Description: Structural basis for KIT receptor inhibition by antibo...

2013-05-02T07:13:01Z

New page: '''Unreleased structure''' The entry 4k9e is ON HOLD Authors: Resheynyak, A.V., Boggon T.J., Lax I., Schlessinger J. Description: Structural basis for KIT receptor inhibition by antibo...

New page

'''Unreleased structure'''

The entry 4k9e is ON HOLD

Authors: Resheynyak, A.V., Boggon T.J., Lax I., Schlessinger J.

Description: Structural basis for KIT receptor inhibition by antibodies targeting the D4 membrane proximal region