View source for 3rpy


==CDK2 in complex with inhibitor RC-2-40==
<StructureSection load='3rpy' size='340' side='right' caption='[[3rpy]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3rpy]] 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=3RPY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RPY FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=27Z:4-AMINO-2-[(4-SULFAMOYLPHENYL)AMINO]-1,3-THIAZOLE-5-CARBOXAMIDE'>27Z</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ql8|3ql8]], [[3qqf|3qqf]], [[3qqg|3qqg]], [[3qqh|3qqh]], [[3qqj|3qqj]], [[3qqk|3qqk]], [[3qql|3qql]], [[3qrt|3qrt]], [[3qru|3qru]], [[3qtq|3qtq]], [[3qtr|3qtr]], [[3qts|3qts]], [[3qtu|3qtu]], [[3qtw|3qtw]], [[3qtx|3qtx]], [[3qtz|3qtz]], [[3qu0|3qu0]], [[3qwj|3qwj]], [[3qwk|3qwk]], [[3qx2|3qx2]], [[3qx4|3qx4]], [[3qxo|3qxo]], [[3qxp|3qxp]], [[3qzf|3qzf]], [[3qzg|3qzg]], [[3qzh|3qzh]], [[3qzi|3qzi]], [[3r1q|3r1q]], [[3r1s|3r1s]], [[3r1y|3r1y]], [[3r28|3r28]], [[3r6x|3r6x]], [[3r71|3r71]], [[3r73|3r73]], [[3r7e|3r7e]], [[3r7i|3r7i]], [[3r7u|3r7u]], [[3r7v|3r7v]], [[3r7y|3r7y]], [[3r83|3r83]], [[3r8l|3r8l]], [[3r8m|3r8m]], [[3r8p|3r8p]], [[3r8u|3r8u]], [[3r8v|3r8v]], [[3r8z|3r8z]], [[3r9d|3r9d]], [[3r9h|3r9h]], [[3r9n|3r9n]], [[3r9o|3r9o]], [[3rah|3rah]], [[3rai|3rai]], [[3rak|3rak]], [[3ral|3ral]], [[3rjc|3rjc]], [[3rk5|3rk5]], [[3rk7|3rk7]], [[3rk9|3rk9]], [[3rkb|3rkb]], [[3rm6|3rm6]], [[3rm7|3rm7]], [[3rmf|3rmf]], [[3rni|3rni]], [[3roy|3roy]], [[3rpo|3rpo]], [[3rpr|3rpr]], [[3rpv|3rpv]], [[3rzb|3rzb]], [[3s00|3s00]], [[3s0o|3s0o]], [[3s1h|3s1h]], [[3sqq|3sqq]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDK2 ([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/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=3rpy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rpy OCA], [http://pdbe.org/3rpy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3rpy RCSB], [http://www.ebi.ac.uk/pdbsum/3rpy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3rpy 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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 muM) from a single hit compound with weak inhibitory activity (IC50 = 15 muM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 muM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.

Development of Highly Potent and Selective Diaminothiazole Inhibitors of Cyclin-Dependent Kinases.,Schonbrunn E, Betzi S, Alam R, Martin MP, Becker A, Han H, Francis R, Chakrasali R, Jakkaraj S, Kazi A, Sebti SM, Cubitt CL, Gebhard AW, Hazlehurst LA, Tash JS, Georg GI J Med Chem. 2013 May 6. PMID:23600925<ref>PMID:23600925</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3rpy" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cyclin-dependent kinase|Cyclin-dependent kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Cyclin-dependent kinase]]
[[Category: Human]]
[[Category: Alam, R]]
[[Category: Becker, A]]
[[Category: Betzi, S]]
[[Category: Han, H]]
[[Category: Schonbrunn, E]]
[[Category: Inhibitor]]
[[Category: Protein kinase]]
[[Category: Transferase-transferase inhibitor complex]]