Modeling the interaction between the N-terminal domain of the tumor suppressor p53 and azurin.
It is known that the half life of the tumor suppressor p53 can be increased by the interaction with the bacterial protein azurin, resulting in an enhanced anti-tumoral activity. The understanding of the molecular mechanisms on the basis of this phenomenon can open the way to new anti-cancer strategies. Some experimental works have given evidence of an interaction between p53 and azurin (AZ); however the binding regions of the proteins are still unknown. Recently, fluorescence studies have shown that p53 partakes in the binding with the bacterial protein by its N-terminal (NT) domain. Here we have used a computational method to get insight into this interacting mode. The model that we propose for the best complex between AZ and p53 has been obtained from a rigid-body docking, coupled with a molecular dynamics (MD) simulation, a free energy calculation, and validated by mutagenesis analysis. We have found a high degree of geometric fit between the two proteins that are kept together by several hydrophobic interactions and numerous hydrogen bonds. Interestingly, it has emerged that AZ binds essentially to the helices H(I) and H(III) of the p53 NT domain, which are also interacting regions for the foremost inhibitor of p53, MDM2.
Taranta
Monia
M
Biophysics and Nanoscience Centre, CNISM, Facoltà di Scienze, Università della Tuscia, Largo dell'Università 01100, Viterbo, Italy.
Bizzarri
Anna Rita
AR
Cannistraro
Salvatore
S
D001400:Azurin / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
D050505:Mutant Proteins; D016159:Tumor Suppressor Protein p53; D001400:Azurin