5amn - Revision history

OCA at 08:42, 23 October 2024

2024-10-23T08:42:54Z

← Older revision		Revision as of 08:42, 23 October 2024
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	==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 11:13, 10 January 2024

2024-01-10T11:13:30Z

← Older revision		Revision as of 11:13, 10 January 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5amn]] 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=5AMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AMN FirstGlance]. <br>		<table><tr><td colspan='2'>[[5amn]] 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=5AMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AMN FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTQ:4-[3-HYDROXYANILINO]-6,7-DIMETHOXYQUINAZOLINE'>DTQ</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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]] 2.57Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTQ:4-[3-HYDROXYANILINO]-6,7-DIMETHOXYQUINAZOLINE'>DTQ</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=5amn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5amn OCA], [https://pdbe.org/5amn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5amn RCSB], [https://www.ebi.ac.uk/pdbsum/5amn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5amn 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=5amn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5amn OCA], [https://pdbe.org/5amn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5amn RCSB], [https://www.ebi.ac.uk/pdbsum/5amn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5amn ProSAT]</span></td></tr>
	</table>		</table>

OCA at 06:15, 31 May 2023

2023-05-31T06:15:19Z

Show changes

OCA at 08:42, 11 March 2020

2020-03-11T08:42:08Z

← Older revision		Revision as of 08:42, 11 March 2020
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	==The Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase Inhibitors==		==The Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase Inhibitors==
	<StructureSection load='5amn' size='340' side='right' caption='[[5amn]], [[Resolution\|resolution]] 2.57Å' scene=''>		<StructureSection load='5amn' size='340' side='right'caption='[[5amn]], [[Resolution\|resolution]] 2.57Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5amn]] 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=5AMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AMN FirstGlance]. <br>		<table><tr><td colspan='2'>[[5amn]] 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=5AMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AMN FirstGlance]. <br>
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	</div>		</div>
	<div class="pdbe-citations 5amn" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5amn" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
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	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
			[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Bowler, K]]		[[Category: Bowler, K]]

OCA at 07:04, 28 February 2018

2018-02-28T07:04:32Z

← Older revision		Revision as of 07:04, 28 February 2018
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	<StructureSection load='5amn' size='340' side='right' caption='[[5amn]], [[Resolution\|resolution]] 2.57Å' scene=''>		<StructureSection load='5amn' size='340' side='right' caption='[[5amn]], [[Resolution\|resolution]] 2.57Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5amn]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AMN FirstGlance]. <br>		<table><tr><td colspan='2'>[[5amn]] 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=5AMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AMN FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTQ:4-[3-HYDROXYANILINO]-6,7-DIMETHOXYQUINAZOLINE'>DTQ</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTQ:4-[3-HYDROXYANILINO]-6,7-DIMETHOXYQUINAZOLINE'>DTQ</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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='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=5amn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5amn OCA], [http://pdbe.org/5amn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5amn RCSB], [http://www.ebi.ac.uk/pdbsum/5amn 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=5amn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5amn OCA], [http://pdbe.org/5amn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5amn RCSB], [http://www.ebi.ac.uk/pdbsum/5amn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5amn ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Bowler, K]]		[[Category: Bowler, K]]

OCA at 06:51, 2 March 2016

2016-03-02T06:51:51Z

← Older revision		Revision as of 06:51, 2 March 2016
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	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/RET_HUMAN RET_HUMAN]] Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration.<ref>PMID:20064382</ref> <ref>PMID:20616503</ref> <ref>PMID:20702524</ref> <ref>PMID:21357690</ref> <ref>PMID:21454698</ref>		[[http://www.uniprot.org/uniprot/RET_HUMAN RET_HUMAN]] Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration.<ref>PMID:20064382</ref> <ref>PMID:20616503</ref> <ref>PMID:20702524</ref> <ref>PMID:21357690</ref> <ref>PMID:21454698</ref>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.

			The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.,Newton R, Bowler KA, Burns EM, Chapman PJ, Fairweather EE, Fritzl SJ, Goldberg KM, Hamilton NM, Holt SV, Hopkins GV, Jones SD, Jordan AM, Lyons AJ, Nikki March H, McDonald NQ, Maguire LA, Mould DP, Purkiss AG, Small HF, Stowell AI, Thomson GJ, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ Eur J Med Chem. 2016 Jan 29;112:20-32. doi: 10.1016/j.ejmech.2016.01.039. PMID:26874741<ref>PMID:26874741</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 5amn" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 02:51, 21 February 2016

2016-02-21T02:51:46Z

Show changes

OCA at 09:49, 16 December 2015

2015-12-16T09:49:44Z

← Older revision		Revision as of 09:49, 16 December 2015
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	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Waszkowycz, B]]		[[Category: Waszkowycz, B]]
			[[Category: Hamilton, N.M]]
			[[Category: Fairweather, E]]
	[[Category: Goldberg, K]]		[[Category: Goldberg, K]]
	[[Category: Newton, R]]		[[Category: Newton, R]]
			[[Category: Lyons, A]]
	[[Category: Mcdonald, N.Q]]		[[Category: Mcdonald, N.Q]]
	[[Category: Waddell, I.D]]		[[Category: Waddell, I.D]]
			[[Category: Bowler, K]]
			[[Category: Stowell, A]]
	[[Category: Purkiss, A.G]]		[[Category: Purkiss, A.G]]
	[[Category: Jones, S.D]]		[[Category: Jones, S.D]]
			[[Category: Hopkins, G.V]]
	[[Category: Small, H.F]]		[[Category: Small, H.F]]
	[[Category: Ogilvie, D.J]]		[[Category: Ogilvie, D.J]]
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	[[Category: Jordan, A.M]]		[[Category: Jordan, A.M]]
	[[Category: Holt, S.V]]		[[Category: Holt, S.V]]
	~~[[Category: Hamilton, N.M]]~~
	~~[[Category: Fairweather, E]]~~
	~~[[Category: Lyons, A]]~~
	~~[[Category: Bowler, K]]~~
	~~[[Category: Stowell, A]]~~
	~~[[Category: Hopkins, G.V]]~~
	[[Category: Chapman, P]]		[[Category: Chapman, P]]
	[[Category: Burns, E.M]]		[[Category: Burns, E.M]]
	[[Category: Mould, D.P]]		[[Category: Mould, D.P]]

OCA at 09:55, 2 September 2015

2015-09-02T09:55:30Z

← Older revision		Revision as of 09:55, 2 September 2015
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 5amn is ON HOLD		The entry 5amn is ON HOLD until Paper Publication

	Authors: Newton, R., Bowler, K., Burns, E.M., Chapman, P., Fairweather, E., Fritzl, S., Goldberg, K., Hamilton, N.M., Holt, S.V., Hopkins, G.V., Jones, S.D., Jordan, A.M., Lyons, A., McDonald, N.Q., Maguire, L.A., Mould, D.P., Purkiss, A.G., Small, H.F., Stowell, A., Thomson, G.J., Waddell, I.D., Waszkowycz, B., Watson, A.J., Ogilvie, D.J.		Authors: Newton, R., Bowler, K., Burns, E.M., Chapman, P., Fairweather, E., Fritzl, S., Goldberg, K., Hamilton, N.M., Holt, S.V., Hopkins, G.V., Jones, S.D., Jordan, A.M., Lyons, A., McDonald, N.Q., Maguire, L.A., Mould, D.P., Purkiss, A.G., Small, H.F., Stowell, A., Thomson, G.J., Waddell, I.D., Waszkowycz, B., Watson, A.J., Ogilvie, D.J.

OCA: Protected "5amn" [edit=sysop:move=sysop]

2015-03-18T11:15:20Z

Protected "5amn" [edit=sysop:move=sysop]

← Older revision	Revision as of 11:15, 18 March 2015
(No difference)