1uol
From Proteopedia
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==Overview== | ==Overview== | ||
Most of the cancer-associated mutations in the tumor suppressor p53 map to, its DNA-binding core domain. Many of them inactivate p53 by decreasing its, thermodynamic stability. We have previously designed the superstable, quadruple mutant M133L/V203A/N239Y/N268D containing the second-site, suppressor mutations N239Y and N268D, which specifically restore activity, and stability in several oncogenic mutants. Here we present the x-ray, structure of this quadruple mutant at 1.9 A resolution, which was solved, in a new crystal form in the absence of DNA. This structure reveals that, the four point mutations cause only small local structural changes, whereas the overall structure of the central beta-sandwich and the, DNA-binding surface is conserved. The suppressor mutation N268D results in, an altered hydrogen bond pattern connecting strands S1 and S10, thus, bridging the two sheets of the beta-sandwich scaffold in an energetically, more favorable way. The second suppressor mutation N239Y, which is located, in close proximity to the DNA-binding surface in loop L3, seems to reduce, the plasticity of the structure in large parts of loop L3 as indicated by, decreased crystallographic temperature factors. The same is observed for, residues in the vicinity of the N268D substitution. This increase in, rigidity provides the structural basis for the increase in thermostability, and an understanding how N268D and N239Y rescue some of the common cancer, mutants. | Most of the cancer-associated mutations in the tumor suppressor p53 map to, its DNA-binding core domain. Many of them inactivate p53 by decreasing its, thermodynamic stability. We have previously designed the superstable, quadruple mutant M133L/V203A/N239Y/N268D containing the second-site, suppressor mutations N239Y and N268D, which specifically restore activity, and stability in several oncogenic mutants. Here we present the x-ray, structure of this quadruple mutant at 1.9 A resolution, which was solved, in a new crystal form in the absence of DNA. This structure reveals that, the four point mutations cause only small local structural changes, whereas the overall structure of the central beta-sandwich and the, DNA-binding surface is conserved. The suppressor mutation N268D results in, an altered hydrogen bond pattern connecting strands S1 and S10, thus, bridging the two sheets of the beta-sandwich scaffold in an energetically, more favorable way. The second suppressor mutation N239Y, which is located, in close proximity to the DNA-binding surface in loop L3, seems to reduce, the plasticity of the structure in large parts of loop L3 as indicated by, decreased crystallographic temperature factors. The same is observed for, residues in the vicinity of the N268D substitution. This increase in, rigidity provides the structural basis for the increase in thermostability, and an understanding how N268D and N239Y rescue some of the common cancer, mutants. | ||
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| + | ==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: tumor suppressor]] | [[Category: tumor suppressor]] | ||
| - | ''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 19:37:06 2007'' |
Revision as of 17:30, 12 November 2007
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CRYSTAL STRUCTURE OF THE HUMAN P53 CORE DOMAIN MUTANT M133L/V203A/N239Y/N268D AT 1.9 A RESOLUTION.
Contents |
Overview
Most of the cancer-associated mutations in the tumor suppressor p53 map to, its DNA-binding core domain. Many of them inactivate p53 by decreasing its, thermodynamic stability. We have previously designed the superstable, quadruple mutant M133L/V203A/N239Y/N268D containing the second-site, suppressor mutations N239Y and N268D, which specifically restore activity, and stability in several oncogenic mutants. Here we present the x-ray, structure of this quadruple mutant at 1.9 A resolution, which was solved, in a new crystal form in the absence of DNA. This structure reveals that, the four point mutations cause only small local structural changes, whereas the overall structure of the central beta-sandwich and the, DNA-binding surface is conserved. The suppressor mutation N268D results in, an altered hydrogen bond pattern connecting strands S1 and S10, thus, bridging the two sheets of the beta-sandwich scaffold in an energetically, more favorable way. The second suppressor mutation N239Y, which is located, in close proximity to the DNA-binding surface in loop L3, seems to reduce, the plasticity of the structure in large parts of loop L3 as indicated by, decreased crystallographic temperature factors. The same is observed for, residues in the vicinity of the N268D substitution. This increase in, rigidity provides the structural basis for the increase in thermostability, and an understanding how N268D and N239Y rescue some of the common cancer, mutants.
Disease
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 Structure
1UOL is a Single protein structure of sequence from Homo sapiens with ZN as ligand. Structure known Active Site: ZNA. Full crystallographic information is available from OCA.
Reference
Crystal structure of a superstable mutant of human p53 core domain. Insights into the mechanism of rescuing oncogenic mutations., Joerger AC, Allen MD, Fersht AR, J Biol Chem. 2004 Jan 9;279(2):1291-6. Epub 2003 Oct 8. PMID:14534297
Page seeded by OCA on Mon Nov 12 19:37:06 2007
