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[[Image: | ==STRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH A 6-CYCLOHEXYLMETHYLOXY-2-ANILINO-PURINE INHIBITOR== | ||
<StructureSection load='1oi9' size='340' side='right' caption='[[1oi9]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1oi9]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OI9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1OI9 FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N20:6-CYCLOHEXYLMETHYLOXY-2-(4-HYDROXYANILINO)PURINE'>N20</scene>, <scene name='pdbligand=SGM:MONOTHIOGLYCEROL'>SGM</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | |||
<tr><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]], [[1g5s|1g5s]], [[1gih|1gih]], [[1gii|1gii]], [[1gij|1gij]], [[1gy3|1gy3]], [[1gz8|1gz8]], [[1h00|1h00]], [[1h01|1h01]], [[1h06|1h06]], [[1h07|1h07]], [[1h08|1h08]], [[1h0u|1h0u]], [[1h0v|1h0v]], [[1h0w|1h0w]], [[1h24|1h24]], [[1h25|1h25]], [[1h26|1h26]], [[1h27|1h27]], [[1h28|1h28]], [[1hck|1hck]], [[1hcl|1hcl]], [[1jsv|1jsv]], [[1jvp|1jvp]], [[1ke5|1ke5]], [[1ke6|1ke6]], [[1ke7|1ke7]], [[1ke8|1ke8]], [[1ke9|1ke9]], [[1qmz|1qmz]], [[1fvv|1fvv]], [[1h1p|1h1p]], [[1h1q|1h1q]], [[1h1r|1h1r]], [[1h1s|1h1s]], [[1jst|1jst]], [[1jsu|1jsu]], [[1ogu|1ogu]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1oi9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1oi9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1oi9 RCSB], [http://www.ebi.ac.uk/pdbsum/1oi9 PDBsum]</span></td></tr> | |||
<table> | |||
== 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/oi/1oi9_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/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity. | |||
N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.,Hardcastle IR, Arris CE, Bentley J, Boyle FT, Chen Y, Curtin NJ, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Jewsbury P, Menyerol J, Mesguiche V, Newell DR, Noble ME, Pratt DJ, Wang LZ, Whitfield HJ J Med Chem. 2004 Jul 15;47(15):3710-22. PMID:15239650<ref>PMID:15239650</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Cell | *[[Cell division protein kinase 2|Cell division protein kinase 2]] | ||
*[[Cyclin|Cyclin]] | *[[Cyclin|Cyclin]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
Revision as of 17:02, 28 September 2014
STRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH A 6-CYCLOHEXYLMETHYLOXY-2-ANILINO-PURINE INHIBITORSTRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH A 6-CYCLOHEXYLMETHYLOXY-2-ANILINO-PURINE INHIBITOR
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity. N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.,Hardcastle IR, Arris CE, Bentley J, Boyle FT, Chen Y, Curtin NJ, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Jewsbury P, Menyerol J, Mesguiche V, Newell DR, Noble ME, Pratt DJ, Wang LZ, Whitfield HJ J Med Chem. 2004 Jul 15;47(15):3710-22. PMID:15239650[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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