2j20: Difference between revisions
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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. | ||
==Disease== | |||
Known diseases associated with this structure: Adrenal cortical carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Breast cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Colorectal cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Hepatocellular carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Histiocytoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Li-Fraumeni syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Multiple malignancy syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Nasopharyngeal carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Osteosarcoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Pancreatic cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Thyroid carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: zinc]] | [[Category: zinc]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:50:57 2007'' | ||
Revision as of 23:44, 12 November 2007
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HUMAN P53 CORE DOMAIN MUTANT M133L-V203A-N239Y-N268D-R273C
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.
DiseaseDisease
Known diseases associated with this structure: Adrenal cortical carcinoma OMIM:[191170], Breast cancer OMIM:[191170], Colorectal cancer OMIM:[191170], Hepatocellular carcinoma OMIM:[191170], Histiocytoma OMIM:[191170], Li-Fraumeni syndrome OMIM:[191170], Multiple malignancy syndrome OMIM:[191170], Nasopharyngeal carcinoma OMIM:[191170], Osteosarcoma OMIM:[191170], Pancreatic cancer OMIM:[191170], Thyroid carcinoma OMIM:[191170]
About this StructureAbout this Structure
2J20 is a Single protein structure of sequence from Homo sapiens with ZN and SO4 as ligands. Structure known Active Site: AC1. 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
- Ang, H.C.
- Fersht, A.R.
- Joerger, A.C.
- SO4
- ZN
- 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