Abstract
As a tumor suppressor protein, p53 plays a crucial role in the cell cycle and in cancer prevention. Almost 50 percent of all human malignant tumors are closely related to a deletion or mutation in p53. The activity of p53 is inhibited by over-active celluar antagonists, especially by the over-expression of the negative regulators MDM2 and MDMX. Protein-protein interactions, or post-translational modifications of the C-terminal negative regulatory domain of p53, also regulate its tumor suppressor activity. Restoration of p53 function through peptide and small molecular inhibitors has become a promising strategy for novel anti-cancer drug design and development. Molecular dynamics simulations have been extensively applied to investigate the conformation changes of p53 induced by protein-protein interactions and protein-ligand interactions, including peptide and small molecular inhibitors. This review focuses on the latest MD simulation research, to provide an overview of the current understanding of interactions between p53 and its partners at an atomic level.
Highlights
Medical Sciences & Peking Union Medical College, Beijing 100730, China; Department of Mathematics and Physics, Shandong Jiaotong University, Jinan 250031, China; These authors contributed to this work
The transcriptional activation domain (TAD) fragment of p53 involving residues 12–26, has high probability of forming a short α-helix that is capable of interacting with protein partners, such as the transformed mouse 3T3 cell double minute 2 (MDM2, or HDM2 for the human congener, PDB ID: 1YCR, Figure 1A) [18] and
This study reveals that electrostatic interaction controls p53-MDM2 complex formation at long range, while van der Waals interactions of Phe19, Trp23, Leu26 of p53 determine the complex formation at short range
Summary
P53 is a tumor suppressor protein, encoded by the P53 gene initially reported in 1979 [1]. p53 is commonly referred to as “the guardian of the genome”, as it plays a vitally important role in multi-cellular organisms, where it regulates the cell cycle (promoting cell apoptosis, maintaining genomic stability and inhibiting tumor angiogenesis) and functions as a tumor suppressor involved in slowing or monitoring the cell division and preventing genome mutation in normal circumstances [2,3,4,5]. The intrinsically disordered C-terminal regulatory domain (CTD), a flexible region is involved in down-regulation of the central DNA binding domain at residues. The TAD fragment of p53 involving residues 12–26, has high probability of forming a short α-helix that is capable of interacting with protein partners, such as the transformed mouse 3T3 cell double minute 2 (MDM2, or HDM2 for the human congener, PDB ID: 1YCR, Figure 1A) [18] and MDM2-related protein (MDMX, named MDM4) [27]. MD simulations discussing the protein-protein interactions and the flexibility of native p53 in TAD, DBD, OD and CTD domains, and the inhibitors (small molecule and peptide inhibitors) are discussed
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