6g35 - Revision history

OCA at 06:02, 16 May 2018

OCA — Wed, 16 May 2018 06:02:58 GMT

←Older revision		Revision as of 06:02, 16 May 2018
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	<StructureSection load='6g35' size='340' side='right' caption='[[6g35]], [[Resolution\|resolution]] 1.55Å' scene=''>		<StructureSection load='6g35' size='340' side='right' caption='[[6g35]], [[Resolution\|resolution]] 1.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6g35]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G35 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G35 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6g35]] 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=6G35 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G35 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=EKK:5-bromotubercidin'>EKK</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=EKK:5-bromotubercidin'>EKK</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6g34\|6g34]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6g34\|6g34]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HASPIN, GSG2 ([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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=6g35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g35 OCA], [http://pdbe.org/6g35 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g35 RCSB], [http://www.ebi.ac.uk/pdbsum/6g35 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g35 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=6g35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g35 OCA], [http://pdbe.org/6g35 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g35 RCSB], [http://www.ebi.ac.uk/pdbsum/6g35 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g35 ProSAT]</span></td></tr>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Arrowsmith, C H]]		[[Category: Arrowsmith, C H]]

OCA at 05:53, 18 April 2018

OCA — Wed, 18 Apr 2018 05:53:15 GMT

←Older revision		Revision as of 05:53, 18 April 2018
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-	'''Unreleased structure'''

-	~~The entry~~ 6g35 is ~~ON HOLD~~	+	==Crystal structure of haspin in complex with 5-bromotubercidin==
		+	<StructureSection load='6g35' size='340' side='right' caption='[[6g35]], [[Resolution\|resolution]] 1.55Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6g35]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G35 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G35 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=EKK:5-bromotubercidin'>EKK</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6g34\|6g34]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=6g35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g35 OCA], [http://pdbe.org/6g35 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g35 RCSB], [http://www.ebi.ac.uk/pdbsum/6g35 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g35 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/HASP_HUMAN HASP_HUMAN]] Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.<ref>PMID:11228240</ref> <ref>PMID:15681610</ref> <ref>PMID:17084365</ref> <ref>PMID:20705812</ref> <ref>PMID:20929775</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Prolonged drug residence times may result in longer lasting drug efficacy, improved pharmacodynamic properties and "kinetic selectivity" over off-targets with fast drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Here, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. This key interaction is dependent on the interactions with an aromatic residue in the gatekeeper position and we observe this interaction in other kinases with an aromatic gatekeeper residue. We provide a detailed mechanistic characterization of the halogen-aromatic pi interactions in the haspin-inhibitor complexes by means of kinetic, thermodynamic, and structural measurements along with binding energy calculations. Since halogens are frequently used in drugs and aromatic residues are often present in the binding sites of proteins, our results provide a compelling rationale for introducing aromatic-halogen interactions to prolong drug-target residence times.

-	~~Authors:~~ Heroven, C., ~~Chaikuad~~, A., ~~Bountra~~, C., ~~Arrowsmith~~, ~~C.H., Edwards~~, A~~.M.~~, Knapp, S.~~, Structural Genomics Consortium (SGC)~~	+	Halogen-aromatic pi-interactions modulate inhibitor residence time.,Heroven C, Georgi V, Ganotra GK, Brennan PE, Wolfreys F, Wade RC, Fernandez-Montalvan AE, Chaikuad A, Knapp S Angew Chem Int Ed Engl. 2018 Mar 30. doi: 10.1002/anie.201801666. PMID:29601130<ref>PMID:29601130</ref>

-	~~Description: Crystal structure~~ of ~~haspin in complex with 5~~-~~bromotubercidin~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 6g35" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Arrowsmith, C H]]
		+	[[Category: Bountra, C]]
	[[Category: Chaikuad, A]]		[[Category: Chaikuad, A]]
-	~~[[Category: Knapp, S]]~~	+	[[Category: Edwards, A M]]
-	[[Category: Edwards, A.M]]	+
-	~~[[Category: Arrowsmith, C.H~~]]	+
	[[Category: Heroven, C]]		[[Category: Heroven, C]]
-	[[Category: Structural ~~Genomics Consortium (~~Sgc)]]	+	[[Category: Knapp, S]]
-	[[Category: ~~Bountra, C~~]]	+	[[Category: Structural genomic]]
		+	[[Category: Halogen]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Kinetic]]
		+	[[Category: Sgc]]
		+	[[Category: Slow off-rate]]
		+	[[Category: Transferase]]

OCA: Protected "6g35" [edit=sysop:move=sysop]

OCA — Wed, 04 Apr 2018 04:49:18 GMT

Protected "6g35" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:49, 4 April 2018

OCA: New page: '''Unreleased structure''' The entry 6g35 is ON HOLD Authors: Heroven, C., Chaikuad, A., Bountra, C., Arrowsmith, C.H., Edwards, A.M., Knapp, S., Structural Genomics Consortium (SGC) D...

OCA — Wed, 04 Apr 2018 04:49:17 GMT

New page: '''Unreleased structure''' The entry 6g35 is ON HOLD Authors: Heroven, C., Chaikuad, A., Bountra, C., Arrowsmith, C.H., Edwards, A.M., Knapp, S., Structural Genomics Consortium (SGC) D...

New page

'''Unreleased structure'''

The entry 6g35 is ON HOLD

Authors: Heroven, C., Chaikuad, A., Bountra, C., Arrowsmith, C.H., Edwards, A.M., Knapp, S., Structural Genomics Consortium (SGC)

Description: Crystal structure of haspin in complex with 5-bromotubercidin
[[Category: Unreleased Structures]]
[[Category: Chaikuad, A]]
[[Category: Knapp, S]]
[[Category: Edwards, A.M]]
[[Category: Arrowsmith, C.H]]
[[Category: Heroven, C]]
[[Category: Structural Genomics Consortium (Sgc)]]
[[Category: Bountra, C]]