The tumor suppressor p53: from structures to drug discovery

Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 fu...

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Bibliographic Details
Published in:Cold Spring Harbor perspectives in biology 2010-06, Vol.2 (6), p.a000919-a000919
Main Authors: Joerger, Andreas C, Fersht, Alan R
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Drug Delivery Systems
Drug Discovery
Gene Expression Regulation - physiology
Humans
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.
ISSN:1943-0264
1943-0264
DOI:10.1101/cshperspect.a000919