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[[Image:3bhv.png|left|200px]]
==Structure of phosphorylated Thr160 CDK2/cyclin A in complex with the inhibitor variolin B==
<StructureSection load='3bhv' size='340' side='right' caption='[[3bhv]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3bhv]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BHV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3BHV 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=SGM:MONOTHIOGLYCEROL'>SGM</scene>, <scene name='pdbligand=VAR:9-AMINO-5-(2-AMINOPYRIMIDIN-4-YL)PYRIDO[3,2 4,5]PYRROLO[1,2-C]PYRIMIDIN-4-OL'>VAR</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">[[3bht|3bht]], [[3bhu|3bhu]]</td></tr>
<tr><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 Homo sapiens]), CCNA2, CCNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 Bos taurus])</td></tr>
<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3bhv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bhv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3bhv RCSB], [http://www.ebi.ac.uk/pdbsum/3bhv 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/bh/3bhv_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 ==
Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.


{{STRUCTURE_3bhv|  PDB=3bhv  |  SCENE=  }}
Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases.,Bettayeb K, Tirado OM, Marionneau-Lambot S, Ferandin Y, Lozach O, Morris JC, Mateo-Lozano S, Drueckes P, Schachtele C, Kubbutat MH, Liger F, Marquet B, Joseph B, Echalier A, Endicott JA, Notario V, Meijer L Cancer Res. 2007 Sep 1;67(17):8325-34. PMID:17804748<ref>PMID:17804748</ref>


===Structure of phosphorylated Thr160 CDK2/cyclin A in complex with the inhibitor variolin B===
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
{{ABSTRACT_PUBMED_17804748}}
 
==About this Structure==
[[3bhv]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BHV OCA].


==See Also==
==See Also==
*[[Cell Division Protein Kinase 2|Cell Division Protein Kinase 2]]
*[[Cell division protein kinase 2|Cell division protein kinase 2]]
*[[Cyclin|Cyclin]]
*[[Cyclin|Cyclin]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:017804748</ref><ref group="xtra">PMID:018232649</ref><references group="xtra"/>
__TOC__
</StructureSection>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Cyclin-dependent kinase]]
[[Category: Cyclin-dependent kinase]]

Revision as of 11:38, 29 September 2014

Structure of phosphorylated Thr160 CDK2/cyclin A in complex with the inhibitor variolin BStructure of phosphorylated Thr160 CDK2/cyclin A in complex with the inhibitor variolin B

Structural highlights

3bhv is a 4 chain structure with sequence from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
NonStd Res:
Related:3bht, 3bhu
Gene:CDK2 (Homo sapiens), CCNA2, CCNA (Bos taurus)
Activity:Cyclin-dependent kinase, with EC number 2.7.11.22
Resources:FirstGlance, OCA, RCSB, PDBsum

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 PubMed

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.

Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases.,Bettayeb K, Tirado OM, Marionneau-Lambot S, Ferandin Y, Lozach O, Morris JC, Mateo-Lozano S, Drueckes P, Schachtele C, Kubbutat MH, Liger F, Marquet B, Joseph B, Echalier A, Endicott JA, Notario V, Meijer L Cancer Res. 2007 Sep 1;67(17):8325-34. PMID:17804748[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Bettayeb K, Tirado OM, Marionneau-Lambot S, Ferandin Y, Lozach O, Morris JC, Mateo-Lozano S, Drueckes P, Schachtele C, Kubbutat MH, Liger F, Marquet B, Joseph B, Echalier A, Endicott JA, Notario V, Meijer L. Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases. Cancer Res. 2007 Sep 1;67(17):8325-34. PMID:17804748 doi:67/17/8325

3bhv, resolution 2.10Å

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