1hck: Difference between revisions

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-[[Image:1hck.gif|left|200px]]<br />
-<applet load="1hck" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1hck, resolution 1.9&Aring;" />
-'''HUMAN CYCLIN-DEPENDENT KINASE 2'''<br />
-==Overview==
+==HUMAN CYCLIN-DEPENDENT KINASE 2==
-Inhibition of the cell cycle is widely considered as a new approach toward, treatment for diseases caused by unregulated cell proliferation, including, cancer. Since cyclin-dependent kinases (CDKs) are key enzymes of cell, cycle control, they are promissing targets for the design and discovery of, drugs with antiproliferative activity. The detailed structural analysis of, CDK2 can provide valuable information for the design of new ligands that, can bind in the ATP binding pocket and inhibit CDK2 activity. For this, objective, the crystal structures of human CDK2 apoenzyme and its ATP, complex were refined to 1.8 and 1.9 A, respectively. The high-resolution, refinement reveals 12 ordered water molecules in the ATP binding pocket of, the apoenzyme and five ordered waters in that of the ATP complex. Despite, a large number of hydrogen bonds between ATP-phosphates and CDK2, binding, studies of cyclic AMP-dependent protein kinase with ATP analogues show, that the triphosphate moiety contributes little and the adenine ring is, most important for binding affinity. Our analysis of CDK2 structural data, hydration of residues in the binding pocket of the apoenzyme, flexibility, of the ligand, and structural differences between the apoenzyme and, CDK2-ATP complex provide an explanation for the results of earlier binding, studies with ATP analogues and a basis for future inhibitor design.
+<StructureSection load='1hck' size='340' side='right'caption='[[1hck]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1hck]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HCK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HCK FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1hck FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hck OCA], [https://pdbe.org/1hck PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hck RCSB], [https://www.ebi.ac.uk/pdbsum/1hck PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hck 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/hc/1hck_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=1hck ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-HCK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG and ATP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HCK OCA].
+*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
+== References ==
-==Reference==
+<references/>
-High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design., Schulze-Gahmen U, De Bondt HL, Kim SH, J Med Chem. 1996 Nov 8;39(23):4540-6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=8917641 8917641]
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: De Bondt HL]]
-[[Category: Bondt, H.L.De.]]
+[[Category: Kim S-H]]
-[[Category: Kim, S.H.]]
+[[Category: Schulze-Gahmen U]]
-[[Category: Schulze-Gahmen, U.]]
-[[Category: ATP]]
-[[Category: MG]]
-[[Category: atp-binding]]
-[[Category: cell cycle]]
-[[Category: cell division]]
-[[Category: mitosis]]
-[[Category: phosphorylation]]
-[[Category: serine/threonine protein kinase]]
-[[Category: transferase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:15:48 2007''