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This article is part of the supplement: Eighth International Conference on Bioinformatics (InCoB2009): Bioinformatics

Open Access Proceedings

Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100

Shubhra Ghosh Dastidar1, David P Lane2 and Chandra S Verma134*

Author Affiliations

1 Bioinformatics Institute (A-STAR), 30 Biopolis Street; #07-01 Matrix, Singapore 138671

2 Institute of Molecular and Cell Biology (A-STAR), Proteos, 61 Biopolis Drive, Singapore 138673

3 Department of Biological Sciences, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077

4 School of Biological Sciences, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798

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BMC Bioinformatics 2009, 10(Suppl 15):S6  doi:10.1186/1471-2105-10-S15-S6

Published: 3 December 2009

Abstract

Background

The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53. In tumours with overexpressed MDM2, the p53-MDM2 interaction can be interrupted by a peptide or small molecule to stabilize p53 as a therapeutic strategy. Structural and biochemical/mutagenesis data show that p53 has 3 hydrophobic residues F19, W23 and L26 that embed into the ligand binding pocket of MDM2 which is highly plastic in nature and can modulate its size to accommodate a variety of ligands. This binding pocket is primarily dependent on the orientation of a particular residue, Y100. We have studied the role of the dynamics of Y100 in p53 recognition.

Results

Molecular dynamics simulations show that the Y100 side chain can be in "open" or "closed" states with only the former enabling complex formation. When both p53 and MDM2 are in near native conformations, complex formation is rapid and is driven by the formation of a hydrogen bond between W23 of p53 and L54 of MDM2 or by the embedding of F19 of p53 into MDM2. The transition of Y100 from "closed" to "open" can increase the size of the binding site. Interconversions between these two states can be induced by the N-terminal region of MDM2 or by the conformations of the p53 peptides.

Conclusion

Molecular dynamics simulations have revealed how the binding of p53 to MDM2 is modulated by the conformational mobility of Y100 which is the gatekeeper residue in MDM2. The mobility of this residue can be modulated by the conformations of p53 and the Nterminal lid region of MDM2.