2j1z: Difference between revisions
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|PDB= 2j1z |SIZE=350|CAPTION= <scene name='initialview01'>2j1z</scene>, resolution 1.8Å | |PDB= 2j1z |SIZE=350|CAPTION= <scene name='initialview01'>2j1z</scene>, resolution 1.8Å | ||
|SITE= <scene name='pdbsite=AC1:Zn+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Zn+Binding+Site+For+Chain+B'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand=ZN:ZINC ION'>ZN</scene> | |LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2j1z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j1z OCA], [http://www.ebi.ac.uk/pdbsum/2j1z PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2j1z RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug. | The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Fersht, A R.]] | [[Category: Fersht, A R.]] | ||
[[Category: Joerger, A C.]] | [[Category: Joerger, A C.]] | ||
[[Category: acetylation]] | [[Category: acetylation]] | ||
[[Category: activator]] | [[Category: activator]] | ||
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[[Category: zinc]] | [[Category: zinc]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:51:57 2008'' | ||
Revision as of 03:51, 31 March 2008
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HUMAN P53 CORE DOMAIN MUTANT M133L-V203A-N239Y-N268D-F270L
OverviewOverview
The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug.
About this StructureAbout this Structure
2J1Z is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for understanding oncogenic p53 mutations and designing rescue drugs., Joerger AC, Ang HC, Fersht AR, Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15056-61. Epub 2006 Oct 2. PMID:17015838
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Single protein
- Fersht, A R.
- Joerger, A C.
- Acetylation
- Activator
- Alternative splicing
- Anti-oncogene
- Apoptosis
- Cell cycle
- Disease mutation
- Dna-binding
- Dna-binding protein
- Glycoprotein
- Host-virus interaction
- Li-fraumeni syndrome
- Metal-binding
- Nuclear protein
- P53 dna-binding domain
- Phosphorylation
- Polymorphism
- Second-site suppressor mutation
- Superstable mutant
- Transcription
- Transcription regulation
- Transferase
- Tumor suppressor
- Zinc