3dog: Difference between revisions

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-{{Seed}}
-[[Image:3dog.jpg|left|200px]]
-<!--
+==Structure of Thr 160 phosphorylated CDK2/cyclin A in complex with the inhibitor N-&-N1==
-The line below this paragraph, containing "STRUCTURE_3dog", creates the "Structure Box" on the page.
+<StructureSection load='3dog' size='340' side='right'caption='[[3dog]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3dog]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://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 [https://proteopedia.org/fgij/fg.htm?mol=3DOG FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
-{{STRUCTURE_3dog|  PDB=3dog  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3dog FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dog OCA], [https://pdbe.org/3dog PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3dog RCSB], [https://www.ebi.ac.uk/pdbsum/3dog PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3dog 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>
+== 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/initialview03.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/main_output.php?pdb_ID=3dog 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 of Thr 160 phosphorylated CDK2/cyclin A in complex with the inhibitor N-&-N1===
+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>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3dog" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_18790752}}, adds the Publication Abstract to the page
+*[[Cyclin 3D structures|Cyclin 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 18790752 is the PubMed ID number.
+*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
--->
+== References ==
-{{ABSTRACT_PUBMED_18790752}}
+<references/>
+__TOC__
-==About this Structure==
+</StructureSection>
-DOG is a [[Protein complex]] structure of sequences 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].
-==Reference==
-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:[http://www.ncbi.nlm.nih.gov/pubmed/18790752 18790752]
 [[Category: Bos taurus]]
-[[Category: Cyclin-dependent kinase]]
 [[Category: Homo sapiens]]
-[[Category: Protein complex]]
+[[Category: Large Structures]]
-[[Category: Echalier, A.]]
+[[Category: Echalier A]]
-[[Category: Endicott, J.]]
+[[Category: Endicott J]]
-[[Category: Atp-binding]]
-[[Category: Cell cycle]]
-[[Category: Cell division]]
-[[Category: Cyclin]]
-[[Category: Cytoplasm]]
-[[Category: Kinase]]
-[[Category: Mitosis]]
-[[Category: Nucleotide-binding]]
-[[Category: Nucleus]]
-[[Category: Phosphoprotein]]
-[[Category: Phosphorylation]]
-[[Category: Polymorphism]]
-[[Category: Ser/thr protein kinase]]
-[[Category: Serine/threonine-protein kinase]]
-[[Category: Transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Oct  1 21:43:17 2008''