View source for 3d07


==Human p53 core domain with hot spot mutation R249S (III)==
<StructureSection load='3d07' size='340' side='right'caption='[[3d07]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3d07]] is a 2 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=3D07 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D07 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=3d07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d07 OCA], [https://pdbe.org/3d07 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d07 RCSB], [https://www.ebi.ac.uk/pdbsum/3d07 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d07 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://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:[https://omim.org/entry/133239 133239].  Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS) [MIM:[https://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:[https://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:[https://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:[https://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:[https://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:[https://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 ==
[https://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> 
== 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/d0/3d07_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=3d07 ConSurf].
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== Publication Abstract from PubMed ==
The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation R249S, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.

Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations.,Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393<ref>PMID:18996393</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3d07" style="background-color:#fffaf0;"></div>

==See Also==
*[[P53 3D structures|P53 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Rozenberg H]]
[[Category: Shakked Z]]
[[Category: Suad O]]