4cfw
From Proteopedia
(Difference between revisions)
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| - | + | ==Structure-based design of C8-substituted O6-cyclohexylmethoxyguanine CDK1 and 2 inhibitors.== | |
| - | + | <StructureSection load='4cfw' size='340' side='right' caption='[[4cfw]], [[Resolution|resolution]] 2.45Å' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[4cfw]] 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=4CFW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CFW FirstGlance]. <br> | |
| - | ==Function== | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SQ9:3-[2-AMINO-6-(CYCLOHEXYLMETHOXY)-7H-PURIN-8-YL]-2-METHYLBENZENESULFONAMIDE'>SQ9</scene></td></tr> |
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1w8c|1w8c]], [[4cfm|4cfm]], [[4cfn|4cfn]], [[4cfu|4cfu]], [[4cfv|4cfv]], [[4cfx|4cfx]]</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=4cfw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cfw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cfw RCSB], [http://www.ebi.ac.uk/pdbsum/4cfw PDBsum]</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. | [[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. | ||
| + | <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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | == | + | ==See Also== |
| - | + | *[[Cell division protein kinase 2|Cell division protein kinase 2]] | |
| - | [[Category: Anscombe, E | + | *[[Cyclin|Cyclin]] |
| - | [[Category: Campbell, A | + | == References == |
| - | [[Category: Cano, C | + | <references/> |
| - | [[Category: Carbain, B | + | __TOC__ |
| - | [[Category: Echalier, A | + | </StructureSection> |
| - | [[Category: Endicott, J | + | [[Category: Human]] |
| - | [[Category: Golding, B T | + | [[Category: Anscombe, E]] |
| - | [[Category: Griffin, R | + | [[Category: Campbell, A]] |
| - | [[Category: Haggerty, K | + | [[Category: Cano, C]] |
| - | [[Category: Hardcastle, I R | + | [[Category: Carbain, B]] |
| - | [[Category: Jewsbury, P | + | [[Category: Echalier, A]] |
| - | [[Category: Newell, D R | + | [[Category: Endicott, J]] |
| - | [[Category: Noble, M E.M | + | [[Category: Golding, B T]] |
| - | [[Category: Paterson, D J | + | [[Category: Griffin, R]] |
| - | [[Category: Roche, C | + | [[Category: Haggerty, K]] |
| - | [[Category: Wang, L Z | + | [[Category: Hardcastle, I R]] |
| + | [[Category: Jewsbury, P]] | ||
| + | [[Category: Newell, D R]] | ||
| + | [[Category: Noble, M E.M]] | ||
| + | [[Category: Paterson, D J]] | ||
| + | [[Category: Roche, C]] | ||
| + | [[Category: Wang, L Z]] | ||
[[Category: Cell cycle]] | [[Category: Cell cycle]] | ||
[[Category: Conformational restraint]] | [[Category: Conformational restraint]] | ||
[[Category: Reversed binding mode]] | [[Category: Reversed binding mode]] | ||
[[Category: Structure-based drug design]] | [[Category: Structure-based drug design]] | ||
Revision as of 22:35, 25 December 2014
Structure-based design of C8-substituted O6-cyclohexylmethoxyguanine CDK1 and 2 inhibitors.
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Categories: Human | Anscombe, E | Campbell, A | Cano, C | Carbain, B | Echalier, A | Endicott, J | Golding, B T | Griffin, R | Haggerty, K | Hardcastle, I R | Jewsbury, P | Newell, D R | Noble, M E.M | Paterson, D J | Roche, C | Wang, L Z | Cell cycle | Conformational restraint | Reversed binding mode | Structure-based drug design
