6guc

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'''Unreleased structure'''
 
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The entry 6guc is ON HOLD until Paper Publication
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==CDK2/CyclinA in complex with SU9516==
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<StructureSection load='6guc' size='340' side='right'caption='[[6guc]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6guc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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 [https://proteopedia.org/fgij/fg.htm?mol=6GUC FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SU9:(3Z)-3-(1H-IMIDAZOL-5-YLMETHYLENE)-5-METHOXY-1H-INDOL-2(3H)-ONE'>SU9</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6guc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6guc OCA], [https://pdbe.org/6guc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6guc RCSB], [https://www.ebi.ac.uk/pdbsum/6guc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6guc ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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Authors: Wood, D.J., Korolchuk, S., Tatum, N.J., Wang, L.Z., Endicott, J.A., Noble, M.E.M., Martin, M.P.
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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>
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Description: CDK2/CyclinA in complex with SU9516
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Endicott, J.A]]
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<div class="pdbe-citations 6guc" style="background-color:#fffaf0;"></div>
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[[Category: Korolchuk, S]]
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[[Category: Tatum, N.J]]
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==See Also==
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[[Category: Wood, D.J]]
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*[[Cyclin 3D structures|Cyclin 3D structures]]
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[[Category: Noble, M.E.M]]
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*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
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[[Category: Wang, L.Z]]
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== References ==
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[[Category: Martin, M.P]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Bos taurus]]
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Endicott JA]]
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[[Category: Korolchuk S]]
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[[Category: Martin MP]]
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[[Category: Noble MEM]]
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[[Category: Tatum NJ]]
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[[Category: Wang LZ]]
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[[Category: Wood DJ]]

Current revision

CDK2/CyclinA in complex with SU9516

PDB ID 6guc

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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