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New page: left|200px<br /><applet load="2ioo" size="350" color="white" frame="true" align="right" spinBox="true" caption="2ioo, resolution 2.02Å" /> '''Crystal structure of...
 
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[[Image:2ioo.gif|left|200px]]<br /><applet load="2ioo" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2ioo, resolution 2.02&Aring;" />
'''Crystal structure of the mouse p53 core domain'''<br />


==Overview==
==Crystal structure of the mouse p53 core domain==
The p53 transcriptional regulator is the most frequently mutated protein, in human cancers and the majority of tumor-derived p53 mutations map to, the central DNA-binding core domain, with a subset of these mutations, resulting in reduced p53 stability. Here, the 1.55 A crystal structure of, the mouse p53 core domain with a molecule of, tris(hydroxymethyl)aminomethane (Tris) bound through multiple hydrogen, bonds to a region of p53 shown to be important for repair of a subset of, tumor-derived p53-stability mutations is reported. Consistent with the, hypothesis that Tris binding stabilizes the p53 core domain, equilibrium, denaturation experiments are presented that demonstrate that Tris binding, increases the thermodynamic stability of the mouse p53 core domain by 3.1, kJ mol(-1) and molecular-dynamic simulations are presented revealing an, overall reduction in root-mean-square deviations of the core domain of 0.7, A when Tris is bound. It is also shown that these crystals of the p53 core, domain are suitable for the multiple-solvent crystal structure approach to, identify other potential binding sites for possible core-domain, stabilization compounds. Analysis of the residue-specific temperature, factors of the high-resolution core-domain structure, coupled with a, comparison with other core-domain structures, also reveals that the L1, H1-S5 and S7-S8 core-domain loops, also shown to mediate various p53, activities, harbor inherent flexibility, suggesting that these regions, might be targets for other p53-stabilizing compounds. Together, these, studies provide a molecular scaffold for the structure-based design of, p53-stabilization compounds for development as possible therapeutic, agents.
<StructureSection load='2ioo' size='340' side='right'caption='[[2ioo]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2ioo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IOO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IOO 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]] 2.02&#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=2ioo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ioo OCA], [https://pdbe.org/2ioo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ioo RCSB], [https://www.ebi.ac.uk/pdbsum/2ioo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ioo ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/P53_MOUSE P53_MOUSE] Note=p53 is found in increased amounts in a wide variety of transformed cells. p53 is frequently mutated or inactivated in many types of cancer.
== Function ==
[https://www.uniprot.org/uniprot/P53_MOUSE P53_MOUSE] 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. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression (By similarity). 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, but seems to have to effect on cell-cycle regulation.<ref>PMID:19556538</ref> <ref>PMID:20673990</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/io/2ioo_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=2ioo ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
2IOO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=ZN:'>ZN</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IOO OCA].
*[[P53 3D structures|P53 3D structures]]
 
== References ==
==Reference==
<references/>
High-resolution structure of the p53 core domain: implications for binding small-molecule stabilizing compounds., Ho WC, Luo C, Zhao K, Chai X, Fitzgerald MX, Marmorstein R, Acta Crystallogr D Biol Crystallogr. 2006 Dec;62(Pt 12):1484-93. Epub 2006, Nov 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17139084 17139084]
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
[[Category: Single protein]]
[[Category: Chai X]]
[[Category: Chai, X.]]
[[Category: Fitzgerald MX]]
[[Category: Fitzgerald, M.X.]]
[[Category: Ho WC]]
[[Category: Ho, W.C.]]
[[Category: Luo C]]
[[Category: Luo, C.]]
[[Category: Marmorstein R]]
[[Category: Marmorstein, R.]]
[[Category: Zhao K]]
[[Category: Zhao, K.]]
[[Category: ZN]]
[[Category: ig fold]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jan 29 20:44:33 2008''

Latest revision as of 12:03, 21 February 2024

Crystal structure of the mouse p53 core domainCrystal structure of the mouse p53 core domain

Structural highlights

2ioo is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.02Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

P53_MOUSE Note=p53 is found in increased amounts in a wide variety of transformed cells. p53 is frequently mutated or inactivated in many types of cancer.

Function

P53_MOUSE 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. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression (By similarity). 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, but seems to have to effect on cell-cycle regulation.[1] [2] [3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Allton K, Jain AK, Herz HM, Tsai WW, Jung SY, Qin J, Bergmann A, Johnson RL, Barton MC. Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11612-6. doi:, 10.1073/pnas.0813177106. Epub 2009 Jun 25. PMID:19556538 doi:10.1073/pnas.0813177106
  2. ↑ Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M, Attardi LD, Regev A, Lander ES, Jacks T, Rinn JL. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010 Aug 6;142(3):409-19. doi: 10.1016/j.cell.2010.06.040. PMID:20673990 doi:10.1016/j.cell.2010.06.040
  3. ↑ Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell. 2012 Jun 22;149(7):1536-48. doi: 10.1016/j.cell.2012.05.014. PMID:22726440 doi:10.1016/j.cell.2012.05.014

2ioo, resolution 2.02Å

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