6guc - Revision history

OCA at 09:29, 30 January 2019

2019-01-30T09:29:27Z

←Older revision		Revision as of 09:29, 30 January 2019
Line 3:		Line 3:
	<StructureSection load='6guc' size='340' side='right' caption='[[6guc]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='6guc' size='340' side='right' caption='[[6guc]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6guc]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GUC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GUC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6guc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GUC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GUC FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SU9:(3Z)-3-(1H-IMIDAZOL-5-YLMETHYLENE)-5-METHOXY-1H-INDOL-2(3H)-ONE'>SU9</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SU9:(3Z)-3-(1H-IMIDAZOL-5-YLMETHYLENE)-5-METHOXY-1H-INDOL-2(3H)-ONE'>SU9</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CDK2, CDKN2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CCNA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </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=6guc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6guc OCA], [http://pdbe.org/6guc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6guc RCSB], [http://www.ebi.ac.uk/pdbsum/6guc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6guc 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=6guc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6guc OCA], [http://pdbe.org/6guc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6guc RCSB], [http://www.ebi.ac.uk/pdbsum/6guc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6guc ProSAT]</span></td></tr>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Bovin]]
	[[Category: Cyclin-dependent kinase]]		[[Category: Cyclin-dependent kinase]]
		+	[[Category: Human]]
	[[Category: Endicott, J A]]		[[Category: Endicott, J A]]
	[[Category: Korolchuk, S]]		[[Category: Korolchuk, S]]

OCA at 06:41, 5 December 2018

2018-12-05T06:41:11Z

←Older revision		Revision as of 06:41, 5 December 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6guc is ~~ON HOLD~~ until ~~Paper~~ Publication	+	==CDK2/CyclinA in complex with SU9516==
		+	<StructureSection load='6guc' size='340' side='right' caption='[[6guc]], [[Resolution\|resolution]] 2.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6guc]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GUC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GUC FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SU9:(3Z)-3-(1H-IMIDAZOL-5-YLMETHYLENE)-5-METHOXY-1H-INDOL-2(3H)-ONE'>SU9</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </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=6guc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6guc OCA], [http://pdbe.org/6guc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6guc RCSB], [http://www.ebi.ac.uk/pdbsum/6guc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6guc ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CDK2_HUMAN CDK2_HUMAN]] Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization.<ref>PMID:10499802</ref> <ref>PMID:11051553</ref> <ref>PMID:10995386</ref> <ref>PMID:10995387</ref> <ref>PMID:10884347</ref> <ref>PMID:11113184</ref> <ref>PMID:15800615</ref> <ref>PMID:18372919</ref> <ref>PMID:20147522</ref> <ref>PMID:20079829</ref> <ref>PMID:20935635</ref> <ref>PMID:20195506</ref> <ref>PMID:19966300</ref> <ref>PMID:21262353</ref> <ref>PMID:21596315</ref> <ref>PMID:21319273</ref> <ref>PMID:17495531</ref> [[http://www.uniprot.org/uniprot/CCNA2_BOVIN CCNA2_BOVIN]] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.

-	~~Authors:~~ Wood~~, D.J.~~, Korolchuk, S., Tatum~~, N.J.~~, Wang~~, L.Z.~~, Endicott~~, J.A.~~, Noble, M.E.M., ~~Martin, M~~.P.	+	Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition.,Wood DJ, Korolchuk S, Tatum NJ, Wang LZ, Endicott JA, Noble MEM, Martin MP Cell Chem Biol. 2018 Nov 1. pii: S2451-9456(18)30375-1. doi:, 10.1016/j.chembiol.2018.10.015. PMID:30472117<ref>PMID:30472117</ref>

-	~~Description~~: ~~CDK2~~/~~CyclinA in complex with SU9516~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Endicott, J.A]]	+	<div class="pdbe-citations 6guc" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Cyclin-dependent kinase]]
		+	[[Category: Endicott, J A]]
	[[Category: Korolchuk, S]]		[[Category: Korolchuk, S]]
-	[[Category: ~~Tatum~~, ~~N.J~~]]	+	[[Category: Martin, M P]]
-	[[Category: ~~Wood~~, D.J]]	+	[[Category: Noble, M E.M]]
-	[[Category: ~~Noble~~, ~~M.E.M~~]]	+	[[Category: Tatum, N J]]
-	[[Category: Wang, L.Z]]	+	[[Category: Wang, L Z]]
-	[[Category: ~~Martin~~, ~~M.P~~]]	+	[[Category: Wood, D J]]
		+	[[Category: Cdk2]]
		+	[[Category: Cell cycle]]
		+	[[Category: Cyclina]]
		+	[[Category: Inhibitor]]

OCA at 04:13, 11 July 2018

2018-07-11T04:13:49Z

←Older revision		Revision as of 04:13, 11 July 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6guc is ON HOLD	+	The entry 6guc is ON HOLD until Paper Publication

	Authors: Wood, D.J., Korolchuk, S., Tatum, N.J., Wang, L.Z., Endicott, J.A., Noble, M.E.M., Martin, M.P.		Authors: Wood, D.J., Korolchuk, S., Tatum, N.J., Wang, L.Z., Endicott, J.A., Noble, M.E.M., Martin, M.P.

-	Description: ~~Differences in the conformational energy landscape of CDK1 and~~ CDK2 ~~suggest a mechanism for achieving selective CDK inhibition~~	+	Description: CDK2/CyclinA in complex with SU9516
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Endicott, J.A]]		[[Category: Endicott, J.A]]
-	[[Category: Martin, M.P]]
-	[[Category: Noble, M.E.M]]
	[[Category: Korolchuk, S]]		[[Category: Korolchuk, S]]
-	[[Category: Wang, L.Z]]
	[[Category: Tatum, N.J]]		[[Category: Tatum, N.J]]
	[[Category: Wood, D.J]]		[[Category: Wood, D.J]]
		+	[[Category: Noble, M.E.M]]
		+	[[Category: Wang, L.Z]]
		+	[[Category: Martin, M.P]]

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

2018-06-27T04:14:13Z

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

←Older revision

Revision as of 04:14, 27 June 2018

OCA: New page: '''Unreleased structure''' The entry 6guc is ON HOLD Authors: Wood, D.J., Korolchuk, S., Tatum, N.J., Wang, L.Z., Endicott, J.A., Noble, M.E.M., Martin, M.P. Description: Differences i...

2018-06-27T04:14:12Z

New page: '''Unreleased structure''' The entry 6guc is ON HOLD Authors: Wood, D.J., Korolchuk, S., Tatum, N.J., Wang, L.Z., Endicott, J.A., Noble, M.E.M., Martin, M.P. Description: Differences i...

New page

'''Unreleased structure'''

The entry 6guc is ON HOLD

Authors: Wood, D.J., Korolchuk, S., Tatum, N.J., Wang, L.Z., Endicott, J.A., Noble, M.E.M., Martin, M.P.

Description: Differences in the conformational energy landscape of CDK1 and CDK2 suggest a mechanism for achieving selective CDK inhibition
[[Category: Unreleased Structures]]
[[Category: Endicott, J.A]]
[[Category: Martin, M.P]]
[[Category: Noble, M.E.M]]
[[Category: Korolchuk, S]]
[[Category: Wang, L.Z]]
[[Category: Tatum, N.J]]
[[Category: Wood, D.J]]