View source for 4cfv


==Structure-based design of C8-substituted O6-cyclohexylmethoxyguanine CDK1 and 2 inhibitors.==
<StructureSection load='4cfv' size='340' side='right'caption='[[4cfv]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cfv]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CFV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CFV FirstGlance]. <br>
</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>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=75X:3-[2-AMINO-6-(CYCLOHEXYLMETHOXY)-7H-PURIN-8-YL]-2-METHYLPHENOL'>75X</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4cfv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cfv OCA], [https://pdbe.org/4cfv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cfv RCSB], [https://www.ebi.ac.uk/pdbsum/4cfv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cfv ProSAT]</span></td></tr>
</table>
== Function ==
[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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O6-cyclohexylmethylguanine derivatives, revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a 'reverse' binding mode where the purine backbone has flipped 180 degrees . This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these 'reverse' binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited sub-micromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.

8-Substituted O6-Cyclohexylmethylguanine CDK2 Inhibitors; Using Structure-Based Inhibitor Design to Optimise an Alternative Binding Mode.,Carbain B, Paterson DJ, Anscombe E, Campbell-Dexter A, Cano C, Echalier A, Endicott J, Golding BT, Haggerty K, Hardcastle IR, Jewsbury PJ, Newell DR, Noble M, Roche C, Wang LZ, Griffin RJ J Med Chem. 2013 Dec 4. PMID:24304238<ref>PMID:24304238</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4cfv" 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: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Anscombe E]]
[[Category: Campbell A]]
[[Category: Cano C]]
[[Category: Carbain B]]
[[Category: Echalier A]]
[[Category: Endicott J]]
[[Category: Golding BT]]
[[Category: Griffin R]]
[[Category: Haggerty K]]
[[Category: Hardcastle IR]]
[[Category: Jewsbury P]]
[[Category: Newell DR]]
[[Category: Noble MEM]]
[[Category: Paterson DJ]]
[[Category: Roche C]]
[[Category: Wang LZ]]