View source for 2cjm


==Mechanism of CDK inhibition by active site phosphorylation: CDK2 Y15p T160p in complex with cyclin A structure==
<StructureSection load='2cjm' size='340' side='right'caption='[[2cjm]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2cjm]] is a 4 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=2CJM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2CJM FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1aq1|1aq1]], [[1b38|1b38]], [[1b39|1b39]], [[1buh|1buh]], [[1ckp|1ckp]], [[1di8|1di8]], [[1dm2|1dm2]], [[1e1v|1e1v]], [[1e1x|1e1x]], [[1e9h|1e9h]], [[1f5q|1f5q]], [[1fin|1fin]], [[1fq1|1fq1]], [[1fvt|1fvt]], [[1fvv|1fvv]], [[1g5s|1g5s]], [[1gih|1gih]], [[1gii|1gii]], [[1gij|1gij]], [[1gy3|1gy3]], [[1gz8|1gz8]], [[1h00|1h00]], [[1h01|1h01]], [[1h07|1h07]], [[1h08|1h08]], [[1h0v|1h0v]], [[1h0w|1h0w]], [[1h1p|1h1p]], [[1h1q|1h1q]], [[1h1r|1h1r]], [[1h1s|1h1s]], [[1h24|1h24]], [[1h25|1h25]], [[1h26|1h26]], [[1h27|1h27]], [[1h28|1h28]], [[1hck|1hck]], [[1hcl|1hcl]], [[1jst|1jst]], [[1jsu|1jsu]], [[1jsv|1jsv]], [[1jvp|1jvp]], [[1ke5|1ke5]], [[1ke6|1ke6]], [[1ke7|1ke7]], [[1ke8|1ke8]], [[1ke9|1ke9]], [[1ogu|1ogu]], [[1oi9|1oi9]], [[1oiq|1oiq]], [[1oir|1oir]], [[1oit|1oit]], [[1oiu|1oiu]], [[1oiy|1oiy]], [[1okv|1okv]], [[1okw|1okw]], [[1ol1|1ol1]], [[1ol2|1ol2]], [[1p2a|1p2a]], [[1p5e|1p5e]], [[1pf8|1pf8]], [[1pkd|1pkd]], [[1pw2|1pw2]], [[1pxi|1pxi]], [[1pxj|1pxj]], [[1pxk|1pxk]], [[1pxl|1pxl]], [[1pxm|1pxm]], [[1pxn|1pxn]], [[1pxo|1pxo]], [[1pxp|1pxp]], [[1pye|1pye]], [[1qmz|1qmz]], [[1r78|1r78]], [[1urc|1urc]], [[1urw|1urw]], [[1v1k|1v1k]], [[1vyw|1vyw]], [[1vyz|1vyz]], [[1w0x|1w0x]], [[1w8c|1w8c]], [[1w98|1w98]], [[1wcc|1wcc]], [[1y8y|1y8y]], [[1y91|1y91]], [[1ykr|1ykr]], [[2a0c|2a0c]], [[2b52|2b52]], [[2b53|2b53]], [[2b54|2b54]], [[2b55|2b55]], [[2bhe|2bhe]], [[2bhh|2bhh]], [[2bkz|2bkz]], [[2bpm|2bpm]], [[2btr|2btr]], [[2bts|2bts]], [[2c4g|2c4g]], [[2c5n|2c5n]], [[2c5o|2c5o]], [[2c5p|2c5p]], [[2c5t|2c5t]], [[2c5v|2c5v]], [[2c5x|2c5x]], [[2c5y|2c5y]], [[2c68|2c68]], [[2c69|2c69]], [[2c6i|2c6i]], [[2c6k|2c6k]], [[2c6l|2c6l]], [[2c6m|2c6m]], [[2c6o|2c6o]], [[2c6t|2c6t]], [[2cch|2cch]], [[2cci|2cci]], [[2exm|2exm]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 2.7.12.1 2.7.11.1, 2.7.11.8, 2.7.11.9, 2.7.11.10, 2.7.11.11, 2.7.11.12, 2.7.11.13, 2.7.11.21, 2.7.11.22, 2.7.11.24, 2.7.11.25, 2.7.11.30 and 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=2cjm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cjm OCA], [http://pdbe.org/2cjm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2cjm RCSB], [http://www.ebi.ac.uk/pdbsum/2cjm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2cjm 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_HUMAN CCNA2_HUMAN]] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions. 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cj/2cjm_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2cjm ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibition of cyclin-dependent kinase 1 (CDK1) activity by Tyr-15 phosphorylation directly regulates entry into mitosis and is an important element in the control of the unperturbed cell cycle. Active site phosphorylation of other members of the CDK family that regulate cell cycle progression instates checkpoints that are fundamental to eukaryotic cell cycle regulation. Kinetic and crystallographic analyses of CDK2-cyclin A complexes reveal that this inhibitory mechanism operates through steric blockade of peptide substrate binding and through the creation of an environment that favors a non-productive conformation of the terminal group of ATP. By contrast, tyrosine phosphorylation of CDK2 alters neither its Km for ATP nor its significant intrinsic ATPase activity. Tyr-15-phosphorylated CDK2 retains trace protein phosphorylation activity that should be considered in quantitative and qualitative cell cycle models.

How tyrosine 15 phosphorylation inhibits the activity of cyclin-dependent kinase 2-cyclin A.,Welburn JP, Tucker JA, Johnson T, Lindert L, Morgan M, Willis A, Noble ME, Endicott JA J Biol Chem. 2007 Feb 2;282(5):3173-81. Epub 2006 Nov 9. PMID:17095507<ref>PMID:17095507</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2cjm" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cyclin 3D structures|Cyclin 3D structures]]
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Transferase]]
[[Category: Endicott, J A]]
[[Category: Johnson, T]]
[[Category: Lindert, L]]
[[Category: Morgan, M]]
[[Category: Noble, M E.M]]
[[Category: Tucker, J]]
[[Category: Welburn, J P.I]]
[[Category: Willis, A]]
[[Category: Atp-binding]]
[[Category: Cell cycle]]
[[Category: Cell division]]
[[Category: Cyclin-dependent kinase]]
[[Category: Mitosis]]
[[Category: Nucleotide-binding]]
[[Category: Phosphorylation]]
[[Category: Regulation]]
[[Category: Serine/threonine-protein kinase]]