6jqr - Revision history

OCA at 10:39, 27 March 2024

OCA — Wed, 27 Mar 2024 10:39:26 GMT

←Older revision		Revision as of 10:39, 27 March 2024
Line 3:		Line 3:
	<StructureSection load='6jqr' size='340' side='right'caption='[[6jqr]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='6jqr' size='340' side='right'caption='[[6jqr]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6jqr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JQR OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6JQR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jqr]] 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=6JQR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JQR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C6F:6-ethyl-3-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide'>C6F</scene>, <scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.2Å</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='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C6F:6-ethyl-3-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide'>C6F</scene>, <scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6jqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jqr OCA], [~~http~~://pdbe.org/6jqr PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6jqr RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6jqr PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6jqr 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=6jqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jqr OCA], [https://pdbe.org/6jqr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jqr RCSB], [https://www.ebi.ac.uk/pdbsum/6jqr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jqr ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN]] Defects in FLT3 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 FLT3 are frequent 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 activation loop of the kinase domain can result in a constitutively activated kinase.<ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:14504097</ref> <ref>PMID:9737679</ref> <ref>PMID:18305215</ref> <ref>PMID:11290608</ref> <ref>PMID:8946930</ref> <ref>PMID:11442493</ref>	+	[https://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN] Defects in FLT3 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 FLT3 are frequent 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 activation loop of the kinase domain can result in a constitutively activated kinase.<ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:14504097</ref> <ref>PMID:9737679</ref> <ref>PMID:18305215</ref> <ref>PMID:11290608</ref> <ref>PMID:8946930</ref> <ref>PMID:11442493</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.<ref>PMID:7507245</ref> <ref>PMID:10080542</ref> <ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:16627759</ref> <ref>PMID:18490735</ref> <ref>PMID:20111072</ref> <ref>PMID:21067588</ref> <ref>PMID:21262971</ref> <ref>PMID:21516120</ref> <ref>PMID:14504097</ref>	+	[https://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.<ref>PMID:7507245</ref> <ref>PMID:10080542</ref> <ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:16627759</ref> <ref>PMID:18490735</ref> <ref>PMID:20111072</ref> <ref>PMID:21067588</ref> <ref>PMID:21262971</ref> <ref>PMID:21516120</ref> <ref>PMID:14504097</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Therapeutic effects of FLT3 inhibitors have been reported in acute myeloid leukemia (AML) with constitutively activating FLT3 mutations, including internal tandem duplication (ITD) and point mutation, which are found in approximately one-third of AML patients. One of the critical issues of treatment with FLT3 inhibitors in FLT3-mutated AML is drug resistance. FLT3 ligand (FL) represents a mechanism of resistance to FLT3 inhibitors, including quizartinib, midostaurin, and sorafenib, in AML cells harboring both wild-type and mutant FLT3 (FLT3 (wt)/FLT3 (mut)). Here, we investigated the effect of FL on the efficacy of gilteritinib, a FLT3 inhibitor, in AML-derived cells in vitro and in mice. In contrast to other FLT3 inhibitors, FL stimulation had little effect on growth inhibition or apoptosis induction by gilteritinib. The antitumor activity of gilteritinib was also comparable between xenograft mouse models injected with FL-expressing and mock MOLM-13 cells. In the FLT3 signaling analyses, gilteritinib inhibited FLT3(wt) and FLT3-ITD to a similar degree in HEK293 and Ba/F3 cells, and similarly suppressed FLT3 downstream signaling molecules (including ERK1/2 and STAT5) in both the presence and absence of FL in MOLM-13 cells. Co-crystal structure analysis showed that gilteritinib bound to the ATP-binding pocket of FLT3. These results suggest that gilteritinib has therapeutic potential in FLT3-mutated AML patients with FL overexpression.	+

-	Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells.,Kawase T, Nakazawa T, Eguchi T, Tsuzuki H, Ueno Y, Amano Y, Suzuki T, Mori M, Yoshida T Oncotarget. 2019 Oct 22;10(58):6111-6123. doi: 10.18632/oncotarget.27222., eCollection 2019 Oct 22. PMID:31692922<ref>PMID:31692922</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 6jqr" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Amano Y]]
-	[[Category: Amano, Y]]	+
-	~~[[Category: Oncoprotein]]~~	+
-	~~[[Category: Protein kinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 15:21, 20 November 2019

OCA — Wed, 20 Nov 2019 15:21:46 GMT

←Older revision		Revision as of 15:21, 20 November 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6jqr is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of FLT3 in complex with gilteritinib==
		+	<StructureSection load='6jqr' size='340' side='right'caption='[[6jqr]], [[Resolution\|resolution]] 2.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6jqr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JQR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JQR FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C6F:6-ethyl-3-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide'>C6F</scene>, <scene name='pdbligand=CXS:3-CYCLOHEXYL-1-PROPYLSULFONIC+ACID'>CXS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6jqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jqr OCA], [http://pdbe.org/6jqr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jqr RCSB], [http://www.ebi.ac.uk/pdbsum/6jqr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jqr ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN]] Defects in FLT3 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 FLT3 are frequent 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 activation loop of the kinase domain can result in a constitutively activated kinase.<ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:14504097</ref> <ref>PMID:9737679</ref> <ref>PMID:18305215</ref> <ref>PMID:11290608</ref> <ref>PMID:8946930</ref> <ref>PMID:11442493</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.<ref>PMID:7507245</ref> <ref>PMID:10080542</ref> <ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:16627759</ref> <ref>PMID:18490735</ref> <ref>PMID:20111072</ref> <ref>PMID:21067588</ref> <ref>PMID:21262971</ref> <ref>PMID:21516120</ref> <ref>PMID:14504097</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Therapeutic effects of FLT3 inhibitors have been reported in acute myeloid leukemia (AML) with constitutively activating FLT3 mutations, including internal tandem duplication (ITD) and point mutation, which are found in approximately one-third of AML patients. One of the critical issues of treatment with FLT3 inhibitors in FLT3-mutated AML is drug resistance. FLT3 ligand (FL) represents a mechanism of resistance to FLT3 inhibitors, including quizartinib, midostaurin, and sorafenib, in AML cells harboring both wild-type and mutant FLT3 (FLT3 (wt)/FLT3 (mut)). Here, we investigated the effect of FL on the efficacy of gilteritinib, a FLT3 inhibitor, in AML-derived cells in vitro and in mice. In contrast to other FLT3 inhibitors, FL stimulation had little effect on growth inhibition or apoptosis induction by gilteritinib. The antitumor activity of gilteritinib was also comparable between xenograft mouse models injected with FL-expressing and mock MOLM-13 cells. In the FLT3 signaling analyses, gilteritinib inhibited FLT3(wt) and FLT3-ITD to a similar degree in HEK293 and Ba/F3 cells, and similarly suppressed FLT3 downstream signaling molecules (including ERK1/2 and STAT5) in both the presence and absence of FL in MOLM-13 cells. Co-crystal structure analysis showed that gilteritinib bound to the ATP-binding pocket of FLT3. These results suggest that gilteritinib has therapeutic potential in FLT3-mutated AML patients with FL overexpression.

-	~~Authors: Amano~~, Y.	+	Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells.,Kawase T, Nakazawa T, Eguchi T, Tsuzuki H, Ueno Y, Amano Y, Suzuki T, Mori M, Yoshida T Oncotarget. 2019 Oct 22;10(58):6111-6123. doi: 10.18632/oncotarget.27222., eCollection 2019 Oct 22. PMID:31692922<ref>PMID:31692922</ref>

-	~~Description: Crystal structure~~ of ~~FLT3 in complex with gilteritinib~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6jqr" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Amano, Y]]		[[Category: Amano, Y]]
		+	[[Category: Oncoprotein]]
		+	[[Category: Protein kinase]]
		+	[[Category: Transferase]]

OCA at 05:35, 21 May 2019

OCA — Tue, 21 May 2019 05:35:06 GMT

←Older revision		Revision as of 05:35, 21 May 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6jqr is ON HOLD	+	The entry 6jqr is ON HOLD until Paper Publication

	Authors: Amano, Y.		Authors: Amano, Y.

OCA: Protected "6jqr" [edit=sysop:move=sysop]

OCA — Wed, 10 Apr 2019 05:23:12 GMT

Protected "6jqr" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:23, 10 April 2019

OCA: New page: '''Unreleased structure''' The entry 6jqr is ON HOLD Authors: Amano, Y. Description: Crystal structure of FLT3 in complex with gilteritinib Category: Unreleased Structures [[Catego...

OCA — Wed, 10 Apr 2019 05:23:10 GMT

New page: '''Unreleased structure''' The entry 6jqr is ON HOLD Authors: Amano, Y. Description: Crystal structure of FLT3 in complex with gilteritinib Category: Unreleased Structures [[Catego...

New page

'''Unreleased structure'''

The entry 6jqr is ON HOLD

Authors: Amano, Y.

Description: Crystal structure of FLT3 in complex with gilteritinib
[[Category: Unreleased Structures]]
[[Category: Amano, Y]]