Targeting the conformational transitions of MDM2 and MDMX: insights into dissimilarities and similarities of p53 recognition.
MDM2 and MDMX are oncogenic homologue proteins that regulate the activity and stability of p53, a tumor suppressor protein involved in more than 50% of human cancers. While the large body of experiments so far accumulated has validated MDM2 as a therapeutically important target for the development of anticancer drugs, it is only recently that MDMX has also become an attractive target for the treatment of tumor cells expressing wild type p53. The availability of structural information of the N-terminal domain of MDM2 in complex with p53-derived peptides and inhibitors, and the very recent disclosure of the crystal structure of the N-terminal domain of MDMX bound to a p53 peptide, offer an unprecedented opportunity to provide insight into the molecular basis of p53 recognition and the identification of discriminating features affecting the binding of the tumor suppressor protein at MDM2 and MDMX. By using coarse graining simulations, in this study we report the exploration of the conformational transitions featured in the pathway leading from the apo-MDM2 and apo-MDMX states to the p53-bound MDM2 and p53-bound MDMX states, respectively. The results have enabled us to identify a pool of diverse conformational states of the oncogenic proteins that affect the binding of p53 and the presence of conserved and non-conserved interactions along the conformational transition pathway that may be exploited in the design of selective and dual modulators of MDM2 and MDMX activity.
Macchiarulo
Antonio
A
Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, via del Liceo 1, Perugia, Italy.
Giacchè
Nicola
N
Carotti
Andrea
A
Baroni
Massimo
M
Cruciani
Gabriele
G
Pellicciari
Roberto
R
D000465:Algorithms; D016000:Cluster Analysis; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015233:Models, Statistical; D009010:Monte Carlo Method; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D012984:Software; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2