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Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain

Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain
Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain
Most p53 mutations associated with cancer are located in its DNA binding domain (DBD). Many structures (X-ray and NMR) of this domain are available in the protein data bank (PDB) and a vast conformational heterogeneity characterizes the various free and complexed states. The major difference between the apo and the holo-complexed states appears to lie in the L1 loop. In particular, the conformations of this loop appear to depend intimately on the sequence of DNA to which it binds. This conclusion builds upon recent observations that implicate the tetramerization and the C-terminal domains (respectively TD and Cter) in DNA binding specificity. Detailed PCA analysis of the most recent collection of DBD structures from the PDB have been carried out. In contrast to recommendations that small molecules/drugs stabilize the flexible L1 loop to rescue mutant p53, our study highlights a need to retain the flexibility of the p53 DNA binding surface (DBS). It is the adaptability of this region that enables p53 to engage in the diverse interactions responsible for its functionality
0887-3585
1443-1461
Ouaray, Zahra
1e9b5915-30d7-4dad-ba2f-13655ff2093c
ElSawy, Karim M.
b082b5f9-3ef9-4b9f-9681-a79d20ef3aa5
Lane, David P.
4a30dd01-4f98-4d97-887b-86186ab33518
Essex, Jonathan
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Verma, Chandra
f4df6096-2033-48f6-92a9-ef71643e5f84
Ouaray, Zahra
1e9b5915-30d7-4dad-ba2f-13655ff2093c
ElSawy, Karim M.
b082b5f9-3ef9-4b9f-9681-a79d20ef3aa5
Lane, David P.
4a30dd01-4f98-4d97-887b-86186ab33518
Essex, Jonathan
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Verma, Chandra
f4df6096-2033-48f6-92a9-ef71643e5f84

Ouaray, Zahra, ElSawy, Karim M., Lane, David P., Essex, Jonathan and Verma, Chandra (2016) Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain. Proteins: Structure, Function, and Bioinformatics, 84 (10), 1443-1461. (doi:10.1002/prot.25089). (PMID:27317883)

Record type: Article

Abstract

Most p53 mutations associated with cancer are located in its DNA binding domain (DBD). Many structures (X-ray and NMR) of this domain are available in the protein data bank (PDB) and a vast conformational heterogeneity characterizes the various free and complexed states. The major difference between the apo and the holo-complexed states appears to lie in the L1 loop. In particular, the conformations of this loop appear to depend intimately on the sequence of DNA to which it binds. This conclusion builds upon recent observations that implicate the tetramerization and the C-terminal domains (respectively TD and Cter) in DNA binding specificity. Detailed PCA analysis of the most recent collection of DBD structures from the PDB have been carried out. In contrast to recommendations that small molecules/drugs stabilize the flexible L1 loop to rescue mutant p53, our study highlights a need to retain the flexibility of the p53 DNA binding surface (DBS). It is the adaptability of this region that enables p53 to engage in the diverse interactions responsible for its functionality

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Accepted/In Press date: 13 June 2016
e-pub ahead of print date: 26 July 2016
Published date: October 2016
Organisations: Computational Systems Chemistry

Identifiers

Local EPrints ID: 402297
URI: http://eprints.soton.ac.uk/id/eprint/402297
ISSN: 0887-3585
PURE UUID: f2f3fe93-2c79-4b9f-b0a0-8f00efb4e71d
ORCID for Jonathan Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 04 Nov 2016 08:57
Last modified: 16 Mar 2024 02:45

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Contributors

Author: Zahra Ouaray
Author: Karim M. ElSawy
Author: David P. Lane
Author: Jonathan Essex ORCID iD
Author: Chandra Verma

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