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4nj3

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{{STRUCTURE_4nj3| PDB=4nj3 | SCENE= }}
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==Modulating the interaction between CDK2 and Cyclin A with a Quinoline-based inhibitor==
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===Modulating the interaction between CDK2 and Cyclin A with a Quinoline-based inhibitor===
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<StructureSection load='4nj3' size='340' side='right' caption='[[4nj3]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24332088}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4nj3]] 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=4NJ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NJ3 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2KD:6-(3-CHLOROPHENYL)-2-{[(2S)-3-(4-HYDROXYPHENYL)-1-METHOXY-1-OXOPROPAN-2-YL]CARBAMOYL}QUINOLINE-4-CARBOXYLIC+ACID'>2KD</scene></td></tr>
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<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene></td></tr>
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<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])</td></tr>
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<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>
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<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=4nj3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nj3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4nj3 RCSB], [http://www.ebi.ac.uk/pdbsum/4nj3 PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A new class of quinoline-based kinase inhibitors has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the monomer CDK2 in an affinity-selection/mass spectrometry-based technique and to perform secondary assays that identified compounds that bound only to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Kd) of the original hit improved from 1 to 0.005muM.
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==Function==
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Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor.,Deng Y, Shipps GW Jr, Zhao L, Siddiqui MA, Popovici-Muller J, Curran PJ, Duca JS, Hruza AW, Fischmann TO, Madison VS, Zhang R, McNemar CW, Mayhood TW, Syto R, Annis A, Kirschmeier P, Lees EM, Parry DA, Windsor WT Bioorg Med Chem Lett. 2014 Jan 1;24(1):199-203. doi: 10.1016/j.bmcl.2013.11.041. , Epub 2013 Nov 23. PMID:24332088<ref>PMID:24332088</ref>
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[[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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4nj3]] 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=4NJ3 OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:024332088</ref><references group="xtra"/><references/>
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*[[Cell division protein kinase 2|Cell division protein kinase 2]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Cyclin-dependent kinase]]
[[Category: Cyclin-dependent kinase]]
[[Category: Human]]
[[Category: Human]]
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[[Category: Fischmann, T O.]]
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[[Category: Fischmann, T O]]
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[[Category: Hruza, A W.]]
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[[Category: Hruza, A W]]
[[Category: Atp-binding]]
[[Category: Atp-binding]]
[[Category: Cancer]]
[[Category: Cancer]]
[[Category: Cell cycle]]
[[Category: Cell cycle]]
[[Category: Cell division]]
[[Category: Cell division]]
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[[Category: Cyclin-dependent kinase]]
 
[[Category: Inhibition]]
[[Category: Inhibition]]
[[Category: Mitosis]]
[[Category: Mitosis]]

Revision as of 18:00, 21 December 2014

Modulating the interaction between CDK2 and Cyclin A with a Quinoline-based inhibitor

4nj3, resolution 1.85Å

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