Molecular mechanism of the interaction between MDM2 and p53

Oliver Schon; Assaf Friedler; Mark Bycroft; Stefan M.V. Freund; Alan R. Fersht

doi:10.1016/S0022-2836(02)00852-5

Molecular mechanism of the interaction between MDM2 and p53

Oliver Schon, Assaf Friedler, Mark Bycroft, Stefan M.V. Freund, Alan R. Fersht^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

282 Scopus citations

Abstract

We have investigated the kinetic and thermodynamic basis of the p53-MDM2 interaction using a set of peptides based on residues 15-29 of p53. Wild-type p53 peptide bound MDM2 with a dissociation constant of 580 nM. Phosphorylation of S15 and S20 did not affect binding, but T18 phosphorylation weakened binding tenfold, indicating that phosphorylation of only T18 is responsible for abrogating p53-MDM2 binding. Truncation to residues 17-26 increased affinity 13-fold, but further truncation to 19-26 abolished binding. NMR studies of the binding of the p53-derived peptides revealed global conformational changes of the overall structure of MDM2, stretching far beyond the binding cleft, indicating significant changes in the domain dynamics of MDM2 upon ligand binding.

Original language	English
Pages (from-to)	491-501
Number of pages	11
Journal	Journal of Molecular Biology
Volume	323
Issue number	3
DOIs	https://doi.org/10.1016/S0022-2836(02)00852-5
State	Published - 2002
Externally published	Yes

Bibliographical note

Funding Information:
We thank Steve Jackson (Cambridge, UK) for his discussion and helpful advice. O.S. is supported by a fellowship from the Friedrich-Ebert-Foundation (GER) and the Medical Research Council (UK). A.F. is supported by a long-term fellowship, no. LT00056/2000-M, from the Human Frontier Science Program Organisation. The work was also partly supported by Cancer Research UK.

Keywords

NMR
Peptide
Phosphorylation

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10.1016/S0022-2836(02)00852-5

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title = "Molecular mechanism of the interaction between MDM2 and p53",

abstract = "We have investigated the kinetic and thermodynamic basis of the p53-MDM2 interaction using a set of peptides based on residues 15-29 of p53. Wild-type p53 peptide bound MDM2 with a dissociation constant of 580 nM. Phosphorylation of S15 and S20 did not affect binding, but T18 phosphorylation weakened binding tenfold, indicating that phosphorylation of only T18 is responsible for abrogating p53-MDM2 binding. Truncation to residues 17-26 increased affinity 13-fold, but further truncation to 19-26 abolished binding. NMR studies of the binding of the p53-derived peptides revealed global conformational changes of the overall structure of MDM2, stretching far beyond the binding cleft, indicating significant changes in the domain dynamics of MDM2 upon ligand binding.",

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note = "Funding Information: We thank Steve Jackson (Cambridge, UK) for his discussion and helpful advice. O.S. is supported by a fellowship from the Friedrich-Ebert-Foundation (GER) and the Medical Research Council (UK). A.F. is supported by a long-term fellowship, no. LT00056/2000-M, from the Human Frontier Science Program Organisation. The work was also partly supported by Cancer Research UK.",

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doi = "10.1016/S0022-2836(02)00852-5",

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AU - Friedler, Assaf

AU - Bycroft, Mark

AU - Freund, Stefan M.V.

AU - Fersht, Alan R.

N1 - Funding Information: We thank Steve Jackson (Cambridge, UK) for his discussion and helpful advice. O.S. is supported by a fellowship from the Friedrich-Ebert-Foundation (GER) and the Medical Research Council (UK). A.F. is supported by a long-term fellowship, no. LT00056/2000-M, from the Human Frontier Science Program Organisation. The work was also partly supported by Cancer Research UK.

PY - 2002

Y1 - 2002

N2 - We have investigated the kinetic and thermodynamic basis of the p53-MDM2 interaction using a set of peptides based on residues 15-29 of p53. Wild-type p53 peptide bound MDM2 with a dissociation constant of 580 nM. Phosphorylation of S15 and S20 did not affect binding, but T18 phosphorylation weakened binding tenfold, indicating that phosphorylation of only T18 is responsible for abrogating p53-MDM2 binding. Truncation to residues 17-26 increased affinity 13-fold, but further truncation to 19-26 abolished binding. NMR studies of the binding of the p53-derived peptides revealed global conformational changes of the overall structure of MDM2, stretching far beyond the binding cleft, indicating significant changes in the domain dynamics of MDM2 upon ligand binding.

AB - We have investigated the kinetic and thermodynamic basis of the p53-MDM2 interaction using a set of peptides based on residues 15-29 of p53. Wild-type p53 peptide bound MDM2 with a dissociation constant of 580 nM. Phosphorylation of S15 and S20 did not affect binding, but T18 phosphorylation weakened binding tenfold, indicating that phosphorylation of only T18 is responsible for abrogating p53-MDM2 binding. Truncation to residues 17-26 increased affinity 13-fold, but further truncation to 19-26 abolished binding. NMR studies of the binding of the p53-derived peptides revealed global conformational changes of the overall structure of MDM2, stretching far beyond the binding cleft, indicating significant changes in the domain dynamics of MDM2 upon ligand binding.

KW - NMR

KW - Peptide

KW - Phosphorylation

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JF - Journal of Molecular Biology

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Molecular mechanism of the interaction between MDM2 and p53

Abstract

Bibliographical note

Keywords

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