4ccb - Revision history

OCA at 12:07, 20 December 2023

2023-12-20T12:07:39Z

←Older revision		Revision as of 12:07, 20 December 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ccb]] 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=4CCB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CCB FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ccb]] 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=4CCB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CCB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OFG:3-[(1R)-1-[5-FLUORANYL-2-(1,2,3-TRIAZOL-2-YL)PHENYL]ETHOXY]-5-(3-METHYL-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE'>OFG</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=OFG:3-[(1R)-1-[5-FLUORANYL-2-(1,2,3-TRIAZOL-2-YL)PHENYL]ETHOXY]-5-(3-METHYL-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE'>OFG</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=4ccb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ccb OCA], [https://pdbe.org/4ccb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ccb RCSB], [https://www.ebi.ac.uk/pdbsum/4ccb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ccb 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=4ccb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ccb OCA], [https://pdbe.org/4ccb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ccb RCSB], [https://www.ebi.ac.uk/pdbsum/4ccb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ccb 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 ==
		+	Crizotinib (1), an ALK receptor tyrosine kinase inhibitor approved by the FDA in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e which was potent across a broad panel of engineered ALK mutant cell lines, showed suitable pre-clinical PK and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).
		+
		+	The design of potent and selective inhibitors to overcome clinical ALK mutations resistant to crizotinib.,Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook A, Cui JJ, Dack KN, Deal JG, Deng YL, Dinh DM, Engstrom LD, He M, Hoffman J, Hoffman RL, Shen H, Johnson P, Kania RS, Lam H, Lam JL, Le P, Li Q, Lingardo L, Liu W, West Lu M, McTigue MA, Palmer CL, Richardson PF, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski SL, Tsaparikos K, Wang H, Zhu H, Zhu J, Zou HY, Edwards M J Med Chem. 2014 Jan 16. PMID:24432909<ref>PMID:24432909</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 4ccb" style="background-color:#fffaf0;"></div>

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

OCA at 17:39, 7 September 2022

2022-09-07T17:39:09Z

←Older revision		Revision as of 17:39, 7 September 2022
Line 3:		Line 3:
	<StructureSection load='4ccb' size='340' side='right'caption='[[4ccb]], [[Resolution\|resolution]] 2.03Å' scene=''>		<StructureSection load='4ccb' size='340' side='right'caption='[[4ccb]], [[Resolution\|resolution]] 2.03Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ccb]] 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=4CCB OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4CCB FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ccb]] 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=4CCB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CCB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OFG:3-[(1R)-1-[5-FLUORANYL-2-(1,2,3-TRIAZOL-2-YL)PHENYL]ETHOXY]-5-(3-METHYL-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE'>OFG</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OFG:3-[(1R)-1-[5-FLUORANYL-2-(1,2,3-TRIAZOL-2-YL)PHENYL]ETHOXY]-5-(3-METHYL-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE'>OFG</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'>[https://proteopedia.org/fgij/fg.htm?mol=4ccb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ccb OCA], [https://pdbe.org/4ccb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ccb RCSB], [https://www.ebi.ac.uk/pdbsum/4ccb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ccb ProSAT]</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=4ccb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ccb OCA], [~~http~~://pdbe.org/4ccb PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ccb RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ccb PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ccb 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;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Crizotinib (1), an ALK receptor tyrosine kinase inhibitor approved by the FDA in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e which was potent across a broad panel of engineered ALK mutant cell lines, showed suitable pre-clinical PK and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).	+
-		+
-	The design of potent and selective inhibitors to overcome clinical ALK mutations resistant to crizotinib.,Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook A, Cui JJ, Dack KN, Deal JG, Deng YL, Dinh DM, Engstrom LD, He M, Hoffman J, Hoffman RL, Shen H, Johnson P, Kania RS, Lam H, Lam JL, Le P, Li Q, Lingardo L, Liu W, West Lu M, McTigue MA, Palmer CL, Richardson PF, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski SL, Tsaparikos K, Wang H, Zhu H, Zhu J, Zou HY, Edwards M J Med Chem. 2014 Jan 16. PMID:24432909<ref>PMID:24432909</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 4ccb" style="background-color:#fffaf0;"></div~~>	+

	==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 Y]]
-	[[Category: Deng, Y]]	+	[[Category: Liu W]]
-	[[Category: Liu, W]]	+	[[Category: McTigue M]]
-	[[Category: McTigue, M]]	+	[[Category: Stewart A]]
-	[[Category: Stewart, A]]	+
-	~~[[Category: Anaplastic lymphoma kinase]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Receptor tyrosine kinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 12:47, 10 May 2019

2019-05-10T12:47:34Z

←Older revision		Revision as of 12:47, 10 May 2019
Line 1:		Line 1:

	==Structure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amine==		==Structure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amine==
-	<StructureSection load='4ccb' size='340' side='right' caption='[[4ccb]], [[Resolution\|resolution]] 2.03Å' scene=''>	+	<StructureSection load='4ccb' size='340' side='right'caption='[[4ccb]], [[Resolution\|resolution]] 2.03Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ccb]] 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=4CCB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CCB FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ccb]] 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=4CCB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CCB FirstGlance]. <br>
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 4ccb" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ccb" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase\|Tyrosine kinase]]
	== References ==		== References ==
	<references/>		<references/>
Line 26:		Line 29:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Brooun, A]]		[[Category: Brooun, A]]

OCA at 20:22, 11 August 2016

2016-08-11T20:22:12Z

←Older revision		Revision as of 20:22, 11 August 2016
Line 1:		Line 1:
-	{{STRUCTURE_4ccb\| PDB=4ccb \| SCENE= }}
-	===Structure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amine===
-	{{ABSTRACT_PUBMED_24432909}}

-	==Disease==	+	==Structure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amine==
		+	<StructureSection load='4ccb' size='340' side='right' caption='[[4ccb]], [[Resolution\|resolution]] 2.03Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4ccb]] 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=4CCB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CCB FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OFG:3-[(1R)-1-[5-FLUORANYL-2-(1,2,3-TRIAZOL-2-YL)PHENYL]ETHOXY]-5-(3-METHYL-1H-PYRAZOL-4-YL)PYRIDIN-2-AMINE'>OFG</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=4ccb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ccb OCA], [http://pdbe.org/4ccb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ccb RCSB], [http://www.ebi.ac.uk/pdbsum/4ccb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ccb ProSAT]</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.		[[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 ==
-	==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>		[[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 ==
		+	Crizotinib (1), an ALK receptor tyrosine kinase inhibitor approved by the FDA in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e which was potent across a broad panel of engineered ALK mutant cell lines, showed suitable pre-clinical PK and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

-	~~==About this Structure==~~	+	The design of potent and selective inhibitors to overcome clinical ALK mutations resistant to crizotinib.,Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook A, Cui JJ, Dack KN, Deal JG, Deng YL, Dinh DM, Engstrom LD, He M, Hoffman J, Hoffman RL, Shen H, Johnson P, Kania RS, Lam H, Lam JL, Le P, Li Q, Lingardo L, Liu W, West Lu M, McTigue MA, Palmer CL, Richardson PF, Sach NW, Smeal T, Smith GL, Stewart AE, Timofeevski SL, Tsaparikos K, Wang H, Zhu H, Zhu J, Zou HY, Edwards M J Med Chem. 2014 Jan 16. PMID:24432909<ref>PMID:24432909</ref>
-	~~[[4ccb]] is a 1 chain structure~~. ~~Full crystallographic information is available from [http://oca~~.~~weizmann~~.~~ac.il~~/~~oca-bin/ocashort?id=4CCB OCA].~~	+

-	~~==Reference==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	<~~ref group~~="~~xtra~~"~~>PMID~~:~~024432909~~</~~ref~~><references ~~group="xtra"~~/><~~references~~/>	+	</div>
		+	<div class="pdbe-citations 4ccb" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Brooun, A.]]	+	[[Category: Brooun, A]]
-	[[Category: Deng, Y.]]	+	[[Category: Deng, Y]]
-	[[Category: Liu, W.]]	+	[[Category: Liu, W]]
-	[[Category: McTigue, M.]]	+	[[Category: McTigue, M]]
-	[[Category: Stewart, A.]]	+	[[Category: Stewart, A]]
	[[Category: Anaplastic lymphoma kinase]]		[[Category: Anaplastic lymphoma kinase]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]
	[[Category: Receptor tyrosine kinase]]		[[Category: Receptor tyrosine kinase]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 07:37, 29 January 2014

2014-01-29T07:37:48Z

←Older revision		Revision as of 07:37, 29 January 2014
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{STRUCTURE_4ccb\| PDB=4ccb \| SCENE= }}
		+	===Structure of the Human Anaplastic Lymphoma Kinase in Complex with 3-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H- pyrazol-4-yl)pyridin-2-amine===
		+	{{ABSTRACT_PUBMED_24432909}}

-	The entry ~~4ccb~~ is ~~ON HOLD~~	+	==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.

-	~~Authors~~: ~~McTigue, M~~., ~~Deng,~~ Y., ~~Liu~~, W., ~~Brooun~~, A., ~~Stewart~~, A.	+	==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>

-	~~Description:~~ Structure ~~of the Human Anaplastic Lymphoma Kinase in Complex with 3-(( R)-~~1-(5-~~fluoro-2-(2H-1~~,2,~~3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H-pyrazol-4-yl)pyridin-2-amine~~	+	==About this Structure==
		+	[[4ccb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CCB OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:024432909</ref><references group="xtra"/><references/>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Brooun, A.]]
		+	[[Category: Deng, Y.]]
		+	[[Category: Liu, W.]]
		+	[[Category: McTigue, M.]]
		+	[[Category: Stewart, A.]]
		+	[[Category: Anaplastic lymphoma kinase]]
		+	[[Category: Inhibitor]]
		+	[[Category: Receptor tyrosine kinase]]
		+	[[Category: Transferase]]

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

2013-11-06T06:40:59Z

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

←Older revision

Revision as of 06:40, 6 November 2013

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

2013-11-06T06:40:58Z

New page: '''Unreleased structure''' The entry 4ccb 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 4ccb 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 3-(( R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl-1H-pyrazol-4-yl)pyridin-2-amine