3dog: Difference between revisions

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-[[Image:3dog.png|left|200px]]
+==Structure of Thr 160 phosphorylated CDK2/cyclin A in complex with the inhibitor N-&-N1==
+<StructureSection load='3dog' size='340' side='right' caption='[[3dog]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3dog]] 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=3DOG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3DOG FirstGlance]. <br>
+</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NNN:(2R)-2-{[4-(BENZYLAMINO)-8-(1-METHYLETHYL)PYRAZOLO[1,5-A][1,3,5]TRIAZIN-2-YL]AMINO}BUTAN-1-OL'>NNN</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>[[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=3dog FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dog OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3dog RCSB], [http://www.ebi.ac.uk/pdbsum/3dog 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/do/3dog_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 ==
+Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report the characterization of N-&amp;-N1, a bioisoster of roscovitine displaying improved antitumoral properties. N-&amp;-N1 shows exquisite selectivity for CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine. Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2 phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&amp;-N1 indicates that N-&amp;-N1 is able to inhibit CDKs in a cellular context. N-&amp;-N1 also down-regulates the expression of RNA polymerase. Cocrystal structures of N-&amp;-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both inhibitors adopt similar binding modes. A competitive assay shows that, compared with (R)-roscovitine, N-&amp;-N1 has reduced affinity for Erk2 and pyridoxal kinase. N-&amp;-N1 triggers cell death in a panel of diverse cell lines. Cell death is accompanied by events characteristic of apoptosis: cytochrome c release, activation of effector caspases, and poly(ADP-ribose) polymerase cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1 antiapoptotic factor were also observed. Studies in mice show that N-&amp;-N1 has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether, these results show that analogues of (R)-roscovitine can be designed with improved antitumor potential.
-{{STRUCTURE_3dog|  PDB=3dog  |  SCENE=  }}
+N-&amp;-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine.,Bettayeb K, Sallam H, Ferandin Y, Popowycz F, Fournet G, Hassan M, Echalier A, Bernard P, Endicott J, Joseph B, Meijer L Mol Cancer Ther. 2008 Sep;7(9):2713-24. PMID:18790752<ref>PMID:18790752</ref>
-===Structure of Thr 160 phosphorylated CDK2/cyclin A in complex with the inhibitor N-&-N1===
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-{{ABSTRACT_PUBMED_18790752}}
-==About this Structure==
-[[3dog]] 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=3DOG OCA].
 ==See Also==
-*[[Cell Division Protein Kinase 2|Cell Division Protein Kinase 2]]
+*[[Cell division protein kinase 2|Cell division protein kinase 2]]
 *[[Cyclin|Cyclin]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:018790752</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Bos taurus]]
 [[Category: Cyclin-dependent kinase]]