2uzd: Difference between revisions

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-{{Seed}}
-[[Image:2uzd.png|left|200px]]
-<!--
+==Crystal structure of human CDK2 complexed with a thiazolidinone inhibitor==
-The line below this paragraph, containing "STRUCTURE_2uzd", creates the "Structure Box" on the page.
+<StructureSection load='2uzd' size='340' side='right'caption='[[2uzd]], [[Resolution|resolution]] 2.72&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'>[[2uzd]] 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=2UZD OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2UZD FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C85:4-{5-[(Z)-(2-IMINO-4-OXO-1,3-THIAZOLIDIN-5-YLIDENE)METHYL]FURAN-2-YL}BENZENESULFONAMIDE'>C85</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>
-{{STRUCTURE_2uzd|  PDB=2uzd  |  SCENE=  }}
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[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]], [[1fvv|1fvv]], [[1g5s|1g5s]], [[1gih|1gih]], [[1gii|1gii]], [[1gij|1gij]], [[1gy3|1gy3]], [[1gz8|1gz8]], [[1h00|1h00]], [[1h01|1h01]], [[1h07|1h07]], [[1h08|1h08]], [[1h0v|1h0v]], [[1h0w|1h0w]], [[1h1p|1h1p]], [[1h1q|1h1q]], [[1h1r|1h1r]], [[1h1s|1h1s]], [[1h24|1h24]], [[1h25|1h25]], [[1h26|1h26]], [[1h27|1h27]], [[1h28|1h28]], [[1hck|1hck]], [[1hcl|1hcl]], [[1jst|1jst]], [[1jsu|1jsu]], [[1jsv|1jsv]], [[1jvp|1jvp]], [[1ke5|1ke5]], [[1ke6|1ke6]], [[1ke7|1ke7]], [[1ke8|1ke8]], [[1ke9|1ke9]], [[1ogu|1ogu]], [[1oi9|1oi9]], [[1oiq|1oiq]], [[1oir|1oir]], [[1oit|1oit]], [[1oiu|1oiu]], [[1oiy|1oiy]], [[1okv|1okv]], [[1okw|1okw]], [[1ol1|1ol1]], [[1ol2|1ol2]], [[1p2a|1p2a]], [[1p5e|1p5e]], [[1pf8|1pf8]], [[1pkd|1pkd]], [[1pw2|1pw2]], [[1pxi|1pxi]], [[1pxj|1pxj]], [[1pxk|1pxk]], [[1pxl|1pxl]], [[1pxm|1pxm]], [[1pxn|1pxn]], [[1pxo|1pxo]], [[1pxp|1pxp]], [[1pye|1pye]], [[1qmz|1qmz]], [[1r78|1r78]], [[1urc|1urc]], [[1urw|1urw]], [[1v1k|1v1k]], [[1vyw|1vyw]], [[1vyz|1vyz]], [[1w0x|1w0x]], [[1w8c|1w8c]], [[1w98|1w98]], [[1wcc|1wcc]], [[1y8y|1y8y]], [[1y91|1y91]], [[1ykr|1ykr]], [[2a0c|2a0c]], [[2a4l|2a4l]], [[2b52|2b52]], [[2b53|2b53]], [[2b54|2b54]], [[2b55|2b55]], [[2bhe|2bhe]], [[2bhh|2bhh]], [[2bkz|2bkz]], [[2bpm|2bpm]], [[2btr|2btr]], [[2bts|2bts]], [[2c4g|2c4g]], [[2c5n|2c5n]], [[2c5o|2c5o]], [[2c5p|2c5p]], [[2c5t|2c5t]], [[2c5v|2c5v]], [[2c5x|2c5x]], [[2c5y|2c5y]], [[2c68|2c68]], [[2c69|2c69]], [[2c6i|2c6i]], [[2c6k|2c6k]], [[2c6l|2c6l]], [[2c6m|2c6m]], [[2c6o|2c6o]], [[2c6t|2c6t]], [[2cch|2cch]], [[2cci|2cci]], [[2cjm|2cjm]], [[2clx|2clx]], [[2exm|2exm]], [[2iw6|2iw6]], [[2iw8|2iw8]], [[2iw9|2iw9]], [[2j9m|2j9m]], [[2jgz|2jgz]], [[2uzb|2uzb]], [[2uue|2uue]], [[2uze|2uze]], [[2uzl|2uzl]], [[2uzn|2uzn]], [[2uzo|2uzo]]</div></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2uzd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uzd OCA], [http://pdbe.org/2uzd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2uzd RCSB], [http://www.ebi.ac.uk/pdbsum/2uzd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2uzd ProSAT]</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.
+== 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/uz/2uzd_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/main_output.php?pdb_ID=2uzd ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.
-===CRYSTAL STRUCTURE OF HUMAN CDK2 COMPLEXED WITH A THIAZOLIDINONE INHIBITOR===
+Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.,Richardson CM, Nunns CL, Williamson DS, Parratt MJ, Dokurno P, Howes R, Borgognoni J, Drysdale MJ, Finch H, Hubbard RE, Jackson PS, Kierstan P, Lentzen G, Moore JD, Murray JB, Simmonite H, Surgenor AE, Torrance CJ Bioorg Med Chem Lett. 2007 Jul 15;17(14):3880-5. Epub 2007 May 6. PMID:17570665<ref>PMID:17570665</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2uzd" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_17570665}}, adds the Publication Abstract to the page
+*[[Cyclin 3D structures|Cyclin 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 17570665 is the PubMed ID number.
+*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
--->
+== References ==
-{{ABSTRACT_PUBMED_17570665}}
+<references/>
+__TOC__
-==About this Structure==
+</StructureSection>
-UZD is a 4 chains structure of sequences 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=2UZD OCA].
+[[Category: Human]]
+[[Category: Large Structures]]
-==Reference==
+[[Category: Dokurno, P]]
-<ref group="xtra">PMID:17570665</ref><references group="xtra"/>
+[[Category: Murray, J B]]
-[[Category: Homo sapiens]]
+[[Category: Richardson, C M]]
-[[Category: Dokurno, P.]]
+[[Category: Surgenor, A E]]
-[[Category: Murray, J B.]]
-[[Category: Richardson, C M.]]
-[[Category: Surgenor, A E.]]
 [[Category: Atp-binding]]
 [[Category: Cdk2]]
@@ Line 36: / Line 51: @@
 [[Category: Kinase]]
 [[Category: Mitosis]]
-[[Category: Nucleotide- binding]]
+[[Category: Nucleotide-binding]]
 [[Category: Phosphorylation]]
 [[Category: Serine/threonine-protein kinase]]
 [[Category: Thiazolidinone ligand]]
 [[Category: Transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 18 06:02:24 2009''