2j1x: Difference between revisions
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|PDB= 2j1x |SIZE=350|CAPTION= <scene name='initialview01'>2j1x</scene>, resolution 1.65Å | |PDB= 2j1x |SIZE=350|CAPTION= <scene name='initialview01'>2j1x</scene>, resolution 1.65Å | ||
|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=2j1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j1x OCA], [http://www.ebi.ac.uk/pdbsum/2j1x PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2j1x 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 03:51:55 2008'' | ||
