4dce - Revision history

OCA at 10:44, 1 March 2024

2024-03-01T10:44:27Z

← Older revision		Revision as of 10:44, 1 March 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dce]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCE FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dce]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0JF:(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE'>0JF</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]] 2.03Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0JF:(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE'>0JF</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=4dce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dce OCA], [https://pdbe.org/4dce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dce RCSB], [https://www.ebi.ac.uk/pdbsum/4dce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dce 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=4dce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dce OCA], [https://pdbe.org/4dce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dce RCSB], [https://www.ebi.ac.uk/pdbsum/4dce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dce 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;">~~
	~~== Publication Abstract from PubMed ==~~
	Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC50 = 0.174 microM) during high throughput screening, with selectivity over the highly related kinase insulin-like growth factor-1 (IGF1R). The X-ray co-crystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.

	Rapid Development of Piperidine Carboxamides as Potent and Selective Anaplastic Lymphoma Kinase Inhibitors.,Bryan MC, Whittington DA, Doherty EM, Falsey JR, Cheng AC, Emkey R, Brake RL, Lewis RT J Med Chem. 2012 Jan 20. PMID:22263917<ref>PMID:22263917</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4dce" style="background-color:#fffaf0;"></div~~>

	==See Also==		==See Also==
	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]		*[[Tyrosine kinase receptor 3D structures\|Tyrosine kinase receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 08:11, 21 September 2022

2022-09-21T08:11:27Z

← Older revision		Revision as of 08:11, 21 September 2022
Line 1:		Line 1:

	==Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor==		==Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor==
	<StructureSection load='4dce' size='340' side='right' caption='[[4dce]], [[Resolution\|resolution]] 2.03Å' scene=''>		<StructureSection load='4dce' size='340' side='right'caption='[[4dce]], [[Resolution\|resolution]] 2.03Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dce]] is a 2 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=4DCE OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4DCE FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dce]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JF:(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE'>0JF</scene~~></td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0JF:(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE'>0JF</scene></td></tr>
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ALK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4dce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dce OCA], [https://pdbe.org/4dce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dce RCSB], [https://www.ebi.ac.uk/pdbsum/4dce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dce 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=4dce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dce OCA], [~~http~~://pdbe.org/4dce PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4dce RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4dce PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4dce 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 22:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4dce" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4dce" 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: ~~Receptor protein-tyrosine kinase~~]]		[[Category: Large Structures]]
	[[Category: Chen, H]]		[[Category: Chen H]]
	[[Category: Epstein~~, L F~~]]		[[Category: Epstein LF]]
	[[Category: Whittington~~, D A]]~~		[[Category: Whittington DA]]
	~~[[Category: Eml4-alk]]~~
	~~[[Category: Inhibitor]]~~
	~~[[Category: Npm-alk]]~~
	~~[[Category: Receptor tyrosine kinase]]~~
	~~[[Category: Transferase-inhibitor complex~~]]

OCA at 07:51, 15 November 2017

2017-11-15T07:51:36Z

← Older revision		Revision as of 07:51, 15 November 2017
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 4dce" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4dce" style="background-color:#fffaf0;"></div>

	~~==See Also==~~
	*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 02:52, 11 December 2016

2016-12-11T02:52:38Z

← Older revision		Revision as of 02:52, 11 December 2016
Line 1:		Line 1:

	==Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor==		==Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor==
	<StructureSection load='4dce' size='340' side='right' caption='[[4dce]], [[Resolution\|resolution]] 2.03Å' scene=''>		<StructureSection load='4dce' size='340' side='right' caption='[[4dce]], [[Resolution\|resolution]] 2.03Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dce]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DCE FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dce]] is a 2 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=4DCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DCE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JF:(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE'>0JF</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JF:(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE'>0JF</scene></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ALK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ALK ([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=4dce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dce OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dce RCSB], [http://www.ebi.ac.uk/pdbsum/4dce 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=4dce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dce OCA], [http://pdbe.org/4dce PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dce RCSB], [http://www.ebi.ac.uk/pdbsum/4dce PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dce 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 4dce" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Homo sapiens~~]]		[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Chen, H]]		[[Category: Chen, H]]

OCA at 07:47, 15 February 2015

2015-02-15T07:47:06Z

← Older revision		Revision as of 07:47, 15 February 2015
Line 1:		Line 1:
	~~{{STRUCTURE_4dce\| PDB=4dce \| SCENE= }}~~		==Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor==
	===Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor===		<StructureSection load='4dce' size='340' side='right' caption='[[4dce]], [[Resolution\|resolution]] 2.03Å' scene=''>
	{~~{ABSTRACT_PUBMED_22263917}~~}		== Structural highlights ==
			<table><tr><td colspan='2'>[[4dce]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DCE FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JF:(3S)-N-(4-METHYLBENZYL)-1-{2-[(3,4,5-TRIMETHOXYPHENYL)AMINO]PYRIMIDIN-4-YL}PIPERIDINE-3-CARBOXAMIDE'>0JF</scene></td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ALK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4dce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dce OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dce RCSB], [http://www.ebi.ac.uk/pdbsum/4dce PDBsum]</span></td></tr>
			</table>
			== 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.
			== 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>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC50 = 0.174 microM) during high throughput screening, with selectivity over the highly related kinase insulin-like growth factor-1 (IGF1R). The X-ray co-crystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.

	~~==Disease==~~		Rapid Development of Piperidine Carboxamides as Potent and Selective Anaplastic Lymphoma Kinase Inhibitors.,Bryan MC, Whittington DA, Doherty EM, Falsey JR, Cheng AC, Emkey R, Brake RL, Lewis RT J Med Chem. 2012 Jan 20. PMID:22263917<ref>PMID:22263917</ref>
	~~[[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.

	~~==Function==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	[[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~~>		</div>

	==~~About this Structure~~==		==See Also==
	[[~~4dce~~]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCE OCA].		*[[Tyrosine kinase\|Tyrosine kinase]]
			== References ==
	==~~Reference~~==		<references/>
	~~<ref group="xtra">PMID:022263917</ref>~~<references ~~group="xtra"~~/><~~references~~/>		__TOC__
			</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Chen, H.]]		[[Category: Chen, H]]
	[[Category: Epstein, L F.]]		[[Category: Epstein, L F]]
	[[Category: Whittington, D A.]]		[[Category: Whittington, D A]]
	[[Category: Eml4-alk]]		[[Category: Eml4-alk]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]

OCA at 11:08, 24 March 2013

2013-03-24T11:08:08Z

← Older revision		Revision as of 11:08, 24 March 2013
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	~~[[Image:4dce.png\|left\|200px]]~~

	~~<!--~~
	~~The line below this paragraph, containing "STRUCTURE_4dce", creates the "Structure Box" on the page.~~
	~~You may change the PDB parameter (which sets the PDB file loaded into the applet)~~
	~~or the SCENE parameter (which sets the initial scene displayed when the page is loaded),~~
	~~or leave the SCENE parameter empty for the default display.~~
	~~-->~~
	{{STRUCTURE_4dce\| PDB=4dce \| SCENE= }}		{{STRUCTURE_4dce\| PDB=4dce \| SCENE= }}

	===Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor===		===Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor===
			{{ABSTRACT_PUBMED_22263917}}

			==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.

	<!--		==Function==
	~~The line below this paragraph~~, ~~{{ABSTRACT_PUBMED_22263917}}~~, ~~adds the Publication Abstract to~~ the ~~page~~		[[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>
	~~(as it appears on PubMed at http:~~//~~www~~.~~pubmed~~.~~gov~~), ~~where 22263917 is~~ the ~~PubMed ID number~~.
	-->
	~~{{ABSTRACT_PUBMED_22263917}}~~

	==About this Structure==		==About this Structure==
Line 22:		Line 13:

	==Reference==		==Reference==
	<ref group="xtra">PMID:022263917</ref><references group="xtra"/>		<ref group="xtra">PMID:022263917</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]

OCA at 08:23, 9 May 2012

2012-05-09T08:23:31Z

← Older revision		Revision as of 08:23, 9 May 2012
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	[[Image:4dce.~~jpg~~\|left\|200px]]		[[Image:4dce.png\|left\|200px]]

	<!--		<!--

OCA at 06:31, 8 February 2012

2012-02-08T06:31:34Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+[[Image:4dce.jpg|left|200px]]
-The entry 4dce is ON HOLD
+<!--
-Authors: Whittington, D.A., Epstein, L.F., Chen, H.
+===Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor===
-Description: Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor

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

2012-01-25T06:11:33Z

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

← Older revision	Revision as of 06:11, 25 January 2012
(No difference)

OCA: New page: '''Unreleased structure''' The entry 4dce is ON HOLD Authors: Whittington, D.A., Epstein, L.F., Chen, H. Description: Crystal structure of human anaplastic lymphoma kinase in complex w...

2012-01-25T06:11:33Z

New page: '''Unreleased structure''' The entry 4dce is ON HOLD Authors: Whittington, D.A., Epstein, L.F., Chen, H. Description: Crystal structure of human anaplastic lymphoma kinase in complex w...

New page

'''Unreleased structure'''

The entry 4dce is ON HOLD

Authors: Whittington, D.A., Epstein, L.F., Chen, H.

Description: Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor