4cli - Revision history

OCA at 12:12, 20 December 2023

2023-12-20T12:12:11Z

← Older revision		Revision as of 12:12, 20 December 2023
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4cli]] 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=4CLI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CLI FirstGlance]. <br>		<table><tr><td colspan='2'>[[4cli]] 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=4CLI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CLI FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</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]] 2.05Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</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=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [https://pdbe.org/4cli PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [https://www.ebi.ac.uk/pdbsum/4cli PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cli 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=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [https://pdbe.org/4cli PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [https://www.ebi.ac.uk/pdbsum/4cli PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cli ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[https://omim.org/entry/613014 613014]]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.		[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[https://omim.org/entry/613014 613014]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
	== Function ==		== Function ==
	[[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.<ref>PMID:11387242</ref> <ref>PMID:11121404</ref> <ref>PMID:11278720</ref> <ref>PMID:11809760</ref> <ref>PMID:12107166</ref> <ref>PMID:12122009</ref> <ref>PMID:15226403</ref> <ref>PMID:15908427</ref> <ref>PMID:16317043</ref> <ref>PMID:17274988</ref> <ref>PMID:16878150</ref>		[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.<ref>PMID:11387242</ref> <ref>PMID:11121404</ref> <ref>PMID:11278720</ref> <ref>PMID:11809760</ref> <ref>PMID:12107166</ref> <ref>PMID:12122009</ref> <ref>PMID:15226403</ref> <ref>PMID:15908427</ref> <ref>PMID:16317043</ref> <ref>PMID:17274988</ref> <ref>PMID:16878150</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 07:20, 14 September 2022

2022-09-14T07:20:43Z

← Older revision		Revision as of 07:20, 14 September 2022
Line 3:		Line 3:
	<StructureSection load='4cli' size='340' side='right'caption='[[4cli]], [[Resolution\|resolution]] 2.05Å' scene=''>		<StructureSection load='4cli' size='340' side='right'caption='[[4cli]], [[Resolution\|resolution]] 2.05Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4cli]] 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=4CLI OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4CLI FirstGlance]. <br>		<table><tr><td colspan='2'>[[4cli]] 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=4CLI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CLI FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</scene~~></td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</scene></td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4clj\|4clj]], [[4cmo\|4cmo]], [[4cmt\|4cmt]], [[4cmu\|4cmu]]</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=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [https://pdbe.org/4cli PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [https://www.ebi.ac.uk/pdbsum/4cli PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cli ProSAT]</span></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/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=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [~~http~~://pdbe.org/4cli PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4cli PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4cli ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[[~~http~~://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[~~http~~://omim.org/entry/613014 613014]]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.		[[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[https://omim.org/entry/613014 613014]]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
	== Function ==		== Function ==
	[[~~http~~://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.<ref>PMID:11387242</ref> <ref>PMID:11121404</ref> <ref>PMID:11278720</ref> <ref>PMID:11809760</ref> <ref>PMID:12107166</ref> <ref>PMID:12122009</ref> <ref>PMID:15226403</ref> <ref>PMID:15908427</ref> <ref>PMID:16317043</ref> <ref>PMID:17274988</ref> <ref>PMID:16878150</ref>		[[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.<ref>PMID:11387242</ref> <ref>PMID:11121404</ref> <ref>PMID:11278720</ref> <ref>PMID:11809760</ref> <ref>PMID:12107166</ref> <ref>PMID:12122009</ref> <ref>PMID:15226403</ref> <ref>PMID:15908427</ref> <ref>PMID:16317043</ref> <ref>PMID:17274988</ref> <ref>PMID:16878150</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 22:

	==See Also==		==See Also==
	*[[Tyrosine kinase\|Tyrosine kinase]]		*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	~~[[Category: Receptor protein-tyrosine kinase]]~~		[[Category: Brooun A]]
	[[Category: Brooun, A]]		[[Category: Deng YL]]
	[[Category: Deng~~, Y L~~]]		[[Category: Liu W]]
	[[Category: Liu, W]]		[[Category: McTigue MA]]
	[[Category: McTigue~~, M A~~]]		[[Category: Stewart AE]]
	[[Category: Stewart~~, A E]]~~
	~~[[Category: Inhibitor]]~~
	~~[[Category: Transferase~~]]

OCA at 09:49, 20 March 2019

2019-03-20T09:49:49Z

← Older revision		Revision as of 09:49, 20 March 2019
Line 1:		Line 1:

	==Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF- 06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).==		==Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF- 06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).==
	<StructureSection load='4cli' size='340' side='right' caption='[[4cli]], [[Resolution\|resolution]] 2.05Å' scene=''>		<StructureSection load='4cli' size='340' side='right'caption='[[4cli]], [[Resolution\|resolution]] 2.05Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4cli]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CLI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CLI FirstGlance]. <br>		<table><tr><td colspan='2'>[[4cli]] 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=4CLI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CLI FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4clj\|4clj]], [[4cmo\|4cmo]], [[4cmt\|4cmt]], [[4cmu\|4cmu]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4clj\|4clj]], [[4cmo\|4cmo]], [[4cmt\|4cmt]], [[4cmu\|4cmu]]</td></tr>
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 4cli" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4cli" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Human]]
			[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Brooun, A]]		[[Category: Brooun, A]]

OCA at 20:19, 11 August 2016

2016-08-11T20:19:57Z

← Older revision		Revision as of 20:19, 11 August 2016
Line 1:		Line 1:

	==Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF- 06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).==		==Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF- 06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).==
	<StructureSection load='4cli' size='340' side='right' caption='[[4cli]], [[Resolution\|resolution]] 2.05Å' scene=''>		<StructureSection load='4cli' size='340' side='right' caption='[[4cli]], [[Resolution\|resolution]] 2.05Å' scene=''>
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	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4clj\|4clj]], [[4cmo\|4cmo]], [[4cmt\|4cmt]], [[4cmu\|4cmu]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4clj\|4clj]], [[4cmo\|4cmo]], [[4cmt\|4cmt]], [[4cmu\|4cmu]]</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=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [http://www.ebi.ac.uk/pdbsum/4cli 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=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [http://pdbe.org/4cli PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [http://www.ebi.ac.uk/pdbsum/4cli PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cli ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	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 4cli" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 13:19, 4 January 2015

2015-01-04T13:19:05Z

← Older revision		Revision as of 13:19, 4 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4cli]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CLI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CLI FirstGlance]. <br>		<table><tr><td colspan='2'>[[4cli]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CLI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CLI FirstGlance]. <br>
	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</scene><br>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5P8:(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-8,4-(METHENO)PYRAZOLO[4,3-H][2,5,11]BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE'>5P8</scene></td></tr>
	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4clj\|4clj]], [[4cmo\|4cmo]], [[4cmt\|4cmt]], [[4cmu\|4cmu]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4clj\|4clj]], [[4cmo\|4cmo]], [[4cmt\|4cmt]], [[4cmu\|4cmu]]</td></tr>
	<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [http://www.ebi.ac.uk/pdbsum/4cli 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=4cli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cli OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cli RCSB], [http://www.ebi.ac.uk/pdbsum/4cli PDBsum]</span></td></tr>
	<table>		</table>
	== Disease ==		== Disease ==
	[[http://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[http://omim.org/entry/613014 613014]]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.		[[http://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[http://omim.org/entry/613014 613014]]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
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	</StructureSection>		</StructureSection>
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Brooun, A.]]		[[Category: Brooun, A]]
	[[Category: Deng, Y L.]]		[[Category: Deng, Y L]]
	[[Category: Liu, W.]]		[[Category: Liu, W]]
	[[Category: McTigue, M A.]]		[[Category: McTigue, M A]]
	[[Category: Stewart, A E.]]		[[Category: Stewart, A E]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 05:14, 25 June 2014

2014-06-25T05:14:58Z

← Older revision		Revision as of 05:14, 25 June 2014
Line 18:		Line 18:
	Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of ALK/ROS1 with pre-clinical brain exposure and broad spectrum potency against ALK-resistant mutations.,Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, Cui JJ, Deal JG, Deng YL, Dinh DM, Engstrom LD, He M, Hoffman JE, Hoffman RL, Huang Q, Kath J, Kania RS, Lam H, Lam JL, Le PT, Lingardo L, Liu W, McTigue MA, Palmer CL, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski SL, Zhu H, Zhu J, Zou HY, Edwards MP J Med Chem. 2014 May 13. PMID:24819116<ref>PMID:24819116</ref>		Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of ALK/ROS1 with pre-clinical brain exposure and broad spectrum potency against ALK-resistant mutations.,Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, Cui JJ, Deal JG, Deng YL, Dinh DM, Engstrom LD, He M, Hoffman JE, Hoffman RL, Huang Q, Kath J, Kania RS, Lam H, Lam JL, Le PT, Lingardo L, Liu W, McTigue MA, Palmer CL, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski SL, Zhu H, Zhu J, Zou HY, Edwards MP J Med Chem. 2014 May 13. PMID:24819116<ref>PMID:24819116</ref>

	From ~~MEDLINEÂ®~~/~~PubMedÂ®~~, 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>
	== References ==		== References ==

OCA at 09:41, 28 May 2014

2014-05-28T09:41:00Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF- 06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).==
-The entry 4cli is ON HOLD  until Paper Publication
+Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of ALK/ROS1 with pre-clinical brain exposure and broad spectrum potency against ALK-resistant mutations.,Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, Cui JJ, Deal JG, Deng YL, Dinh DM, Engstrom LD, He M, Hoffman JE, Hoffman RL, Huang Q, Kath J, Kania RS, Lam H, Lam JL, Le PT, Lingardo L, Liu W, McTigue MA, Palmer CL, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski SL, Zhu H, Zhu J, Zou HY, Edwards MP J Med Chem. 2014 May 13. PMID:24819116<ref>PMID:24819116</ref>
-Authors: McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A.
+From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).
+== References ==

OCA at 08:11, 2 April 2014

2014-04-02T08:11:16Z

← Older revision		Revision as of 08:11, 2 April 2014
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4cli is ON HOLD		The entry 4cli is ON HOLD until Paper Publication

	Authors: McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A.		Authors: McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A.

	Description: Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).		Description: Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).

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

2014-01-22T06:39:44Z

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

← Older revision	Revision as of 06:39, 22 January 2014
(No difference)

OCA: New page: '''Unreleased structure''' The entry 4cli is ON HOLD Authors: McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A. Description: Structure of the Human Anaplastic Lymphoma Kinase in ...

2014-01-22T06:39:43Z

New page: '''Unreleased structure''' The entry 4cli is ON HOLD Authors: McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A. Description: Structure of the Human Anaplastic Lymphoma Kinase in ...

New page

'''Unreleased structure'''

The entry 4cli is ON HOLD

Authors: McTigue, M., Deng, Y., Liu, W., Brooun, A., Stewart, A.

Description: Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).