1h26: Difference between revisions

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-==CDK2/CYCLIN A IN COMPLEX WITH AN 11-RESIDUE RECRUITMENT PEPTIDE FROM P53==
-<StructureSection load='1h26' size='340' side='right' caption='[[1h26]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
+==CDK2/CyclinA in complex with an 11-residue recruitment peptide from p53==
+<StructureSection load='1h26' size='340' side='right'caption='[[1h26]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1h26]] is a 5 chain structure with sequence 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=1H26 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1H26 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1h26]] is a 5 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=1H26 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H26 FirstGlance]. <br>
-</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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.24&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[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]], [[1h06|1h06]], [[1h07|1h07]], [[1h08|1h08]], [[1h0u|1h0u]], [[1h0v|1h0v]], [[1h0w|1h0w]], [[1h1p|1h1p]], [[1h1q|1h1q]], [[1h1r|1h1r]], [[1h1s|1h1s]], [[1h24|1h24]], [[1h25|1h25]], [[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]], [[1qmz|1qmz]], [[1tsr|1tsr]], [[1tup|1tup]], [[1ycq|1ycq]], [[1ycs|1ycs]], [[3sak|3sak]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h26 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h26 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1h26 RCSB], [http://www.ebi.ac.uk/pdbsum/1h26 PDBsum]</span></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=1h26 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h26 OCA], [https://pdbe.org/1h26 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h26 RCSB], [https://www.ebi.ac.uk/pdbsum/1h26 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h26 ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[http://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Note=TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.  Defects in TP53 are a cause of esophageal cancer (ESCR) [MIM:[http://omim.org/entry/133239 133239]].  Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS) [MIM:[http://omim.org/entry/151623 151623]]. LFS is an autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed (PubMed:8118819 and PubMed:8718514) and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.<ref>PMID:10570149</ref> <ref>PMID:1933902</ref> <ref>PMID:1978757</ref> <ref>PMID:2259385</ref> <ref>PMID:1737852</ref> <ref>PMID:1565144</ref> <ref>PMID:7887414</ref> <ref>PMID:8825920</ref> <ref>PMID:9452042</ref> <ref>PMID:10484981</ref>   Defects in TP53 are involved in head and neck squamous cell carcinomas (HNSCC) [MIM:[http://omim.org/entry/275355 275355]]; also known as squamous cell carcinoma of the head and neck.  Defects in TP53 are a cause of lung cancer (LNCR) [MIM:[http://omim.org/entry/211980 211980]]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.  Defects in TP53 are a cause of choroid plexus papilloma (CPLPA) [MIM:[http://omim.org/entry/260500 260500]]. Choroid plexus papilloma is a slow-growing benign tumor of the choroid plexus that often invades the leptomeninges. In children it is usually in a lateral ventricle but in adults it is more often in the fourth ventricle. Hydrocephalus is common, either from obstruction or from tumor secretion of cerebrospinal fluid. If it undergoes malignant transformation it is called a choroid plexus carcinoma. Primary choroid plexus tumors are rare and usually occur in early childhood.<ref>PMID:12085209</ref>   Defects in TP53 are a cause of adrenocortical carcinoma (ADCC) [MIM:[http://omim.org/entry/202300 202300]]. ADCC is a rare childhood tumor of the adrenal cortex. It occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome and is a component tumor in Li-Fraumeni syndrome.<ref>PMID:11481490</ref>   Defects in TP53 are the cause of susceptibility to basal cell carcinoma 7 (BCC7) [MIM:[http://omim.org/entry/614740 614740]]. A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter.<ref>PMID:21946351</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/P53_HUMAN P53_HUMAN]] Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; te function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seem to have to effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis.<ref>PMID:9840937</ref> <ref>PMID:11025664</ref> <ref>PMID:12810724</ref> <ref>PMID:15186775</ref> <ref>PMID:15340061</ref> <ref>PMID:17317671</ref> <ref>PMID:17349958</ref> <ref>PMID:19556538</ref> <ref>PMID:20673990</ref> <ref>PMID:20959462</ref> <ref>PMID:22726440</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.
+[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/h2/1h26_consurf.spt"</scriptWhenChecked>
+     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h2/1h26_consurf.spt"</scriptWhenChecked>
-     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+     <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/chain_selection.php?pdb_ID=2ata ConSurf].
+</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=1h26 ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 29: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 1h26" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Cell division protein kinase 2|Cell division protein kinase 2]]
+*[[Cyclin 3D structures|Cyclin 3D structures]]
-*[[Cyclin|Cyclin]]
+*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
 == References ==
 <references/>
@@ Line 38: / Line 38: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Brown, N R]]
+[[Category: Large Structures]]
-[[Category: Cheng, K Y]]
+[[Category: Brown NR]]
-[[Category: Gamblin, S]]
+[[Category: Cheng KY]]
-[[Category: Gul, S]]
+[[Category: Gamblin S]]
-[[Category: Johnson, L N]]
+[[Category: Gul S]]
-[[Category: Lowe, E D]]
+[[Category: Johnson LN]]
-[[Category: Noble, M E.M]]
+[[Category: Lowe ED]]
-[[Category: Tews, I]]
+[[Category: Noble MEM]]
-[[Category: Cdk2]]
+[[Category: Tews I]]
-[[Category: Cell cycle]]
-[[Category: Cyclin]]
-[[Category: Peptide specificity]]
-[[Category: Protein kinase]]
-[[Category: Recruitment]]