5mrb - Revision history

OCA at 17:46, 8 November 2023

OCA — Wed, 08 Nov 2023 17:46:58 GMT

←Older revision		Revision as of 17:46, 8 November 2023
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	<StructureSection load='5mrb' size='340' side='right'caption='[[5mrb]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='5mrb' size='340' side='right'caption='[[5mrb]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5mrb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MRB OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5MRB FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5mrb]] 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=5MRB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MRB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C5N:~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide'>C5N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene~~></td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.2Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ljj\|5ljj]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C5N:~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide'>C5N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </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=5mrb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mrb OCA], [https://pdbe.org/5mrb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mrb RCSB], [https://www.ebi.ac.uk/pdbsum/5mrb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mrb ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5mrb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mrb OCA], [~~http~~://pdbe.org/5mrb PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5mrb RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5mrb PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5mrb ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN]] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</ref>	+	[https://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Dual-specificity kinase~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Hiruma, Y]]	+	[[Category: Hiruma Y]]
-	[[Category: Joosten~~, R P~~]]	+	[[Category: Joosten RP]]
-	[[Category: Perrakis, A]]	+	[[Category: Perrakis A]]
-	~~[[Category: Compound 5]]~~	+
-	~~[[Category: Cpd-5]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Mps1]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Ttk~~]]	+

OCA at 07:26, 19 August 2020

OCA — Wed, 19 Aug 2020 07:26:41 GMT

←Older revision		Revision as of 07:26, 19 August 2020
Line 1:		Line 1:

	==Crystal structure of human Mps1 (TTK) in complex with Cpd-5==		==Crystal structure of human Mps1 (TTK) in complex with Cpd-5==
-	<StructureSection load='5mrb' size='340' side='right' caption='[[5mrb]], [[Resolution\|resolution]] 2.20Å' scene=''>	+	<StructureSection load='5mrb' size='340' side='right'caption='[[5mrb]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5mrb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MRB OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5MRB FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5mrb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MRB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MRB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C5N:~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide'>C5N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C5N:~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide'>C5N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ljj\|5ljj]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ljj\|5ljj]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </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=5mrb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mrb OCA], [http://pdbe.org/5mrb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mrb RCSB], [http://www.ebi.ac.uk/pdbsum/5mrb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mrb ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5mrb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mrb OCA], [http://pdbe.org/5mrb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mrb RCSB], [http://www.ebi.ac.uk/pdbsum/5mrb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mrb ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
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	</div>		</div>
	<div class="pdbe-citations 5mrb" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5mrb" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Dual specificity protein kinase 3D structures\|Dual specificity protein kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
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	</StructureSection>		</StructureSection>
	[[Category: Dual-specificity kinase]]		[[Category: Dual-specificity kinase]]
		+	[[Category: Large Structures]]
	[[Category: Hiruma, Y]]		[[Category: Hiruma, Y]]
	[[Category: Joosten, R P]]		[[Category: Joosten, R P]]

OCA at 04:04, 4 August 2017

OCA — Fri, 04 Aug 2017 04:04:54 GMT

←Older revision		Revision as of 04:04, 4 August 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5mrb is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of human Mps1 (TTK) in complex with Cpd-5==
		+	<StructureSection load='5mrb' size='340' side='right' caption='[[5mrb]], [[Resolution\|resolution]] 2.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5mrb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MRB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MRB FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C5N:~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide'>C5N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ljj\|5ljj]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </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=5mrb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mrb OCA], [http://pdbe.org/5mrb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mrb RCSB], [http://www.ebi.ac.uk/pdbsum/5mrb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mrb ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN]] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signalling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described. Here we characterize the interactions of two such mutants, Mps1 C604Y and C604W, which raise resistance to two closely related compounds, NMS-P715 and its derivative Cpd-5, but not to the well-characterised Mps1 inhibitor, reversine. We show that estimates of the IC50 (employing a novel specific and efficient assay that utilizes a fluorescently labelled substrate) and of the binding affinity (KD) indicate that in both mutants, Cpd-5 should be better tolerated than the closely related NMS-P715. To gain further insight, we determined the crystal structure of the Mps1 kinase mutants bound to Cpd-5 and NMS-P715, and compare the binding modes of Cpd-5, NMS-P715 and reversine. The difference in steric hindrance between Tyr/Trp604 and the trifluoromethoxy moiety of NMS-P715, the methoxy moiety of Cpd-5, and complete absence of such a group in reversine, account for differences we observe in vitro Our analysis enforces the notion that inhibitors targeting Mps1 drug-resistant mutations can emerge as a feasible intervention strategy based on existing scaffolds, if the clinical need arises.

-	~~Authors: Hiruma~~, Y., ~~Joosten~~, ~~R.P.~~, ~~Perrakis~~, A.	+	Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures.,Hiruma Y, Koch A, Hazraty N, Tsakou F, Medema RH, Joosten RP, Perrakis A J Biol Chem. 2017 Jul 18. pii: jbc.M117.783555. doi: 10.1074/jbc.M117.783555. PMID:28726638<ref>PMID:28726638</ref>

-	~~Description: Crystal structure~~ of ~~human Mps1 (TTK) in complex with Cpd~~-5	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5mrb" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Dual-specificity kinase]]
	[[Category: Hiruma, Y]]		[[Category: Hiruma, Y]]
-	[[Category: Joosten, R.P]]	+	[[Category: Joosten, R P]]
	[[Category: Perrakis, A]]		[[Category: Perrakis, A]]
		+	[[Category: Compound 5]]
		+	[[Category: Cpd-5]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Mps1]]
		+	[[Category: Transferase]]
		+	[[Category: Ttk]]

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

OCA — Wed, 04 Jan 2017 14:18:00 GMT

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

←Older revision

Revision as of 14:18, 4 January 2017

OCA: New page: '''Unreleased structure''' The entry 5mrb is ON HOLD until Paper Publication Authors: Hiruma, Y., Joosten, R.P., Perrakis, A. Description: Crystal structure of human Mps1 (TTK) in comp...

OCA — Wed, 04 Jan 2017 14:17:59 GMT

New page: '''Unreleased structure''' The entry 5mrb is ON HOLD until Paper Publication Authors: Hiruma, Y., Joosten, R.P., Perrakis, A. Description: Crystal structure of human Mps1 (TTK) in comp...

New page

'''Unreleased structure'''

The entry 5mrb is ON HOLD until Paper Publication

Authors: Hiruma, Y., Joosten, R.P., Perrakis, A.

Description: Crystal structure of human Mps1 (TTK) in complex with Cpd-5
[[Category: Unreleased Structures]]
[[Category: Hiruma, Y]]
[[Category: Joosten, R.P]]
[[Category: Perrakis, A]]