TY - JOUR
T1 - Restoration of p53-DNA interaction loss upon R273H mutation by CP-31398
T2 - An ultra accelerated quantum chemical molecular dynamics approach
AU - Rauf, Shah Md Abdur
AU - Sahu, Kamlesh Kumar
AU - Tsuboi, Hideyuki
AU - Hatakeyama, Nozomu
AU - Endou, Akira
AU - Takaba, Hiromitsu
AU - Del Carpio, Carlos A.
AU - Miyamoto, Akira
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/2
Y1 - 2012/2
N2 - The mutation of Arginine273 to Histidine in the DNA binding domain of p53 is one of the most common mutations found in human cancer. Though R273H mutation retains wild-type conformation, the sequence-specific DNA binding is impaired and subsequently lack of transactivation function and the ability to suppress cell growth. CP-31398 can restore DNA binding activity to mutant p53 has shown by a chromatin immunoprecipitation assay but the underlying mechanism at atomistic level is not well understood. Our aim is to investigate theoretically the effect of R273H mutation on DNA binding and the mechanism of restoration of DNA binding by CP-31398, using docking and newly developed ultra accelerated quantum chemical molecular dynamics. Our results show that due to R273H mutation, p53 lost two hydrogen bonds with DNA at the binding site during interaction. CP-31398 helps to reestablish the lost hydrogen bond interactions at p53-DNA binding site, thus restore DNA binding activity and transcriptional activity. This will provide a deeper insight to structure-based drug designing.
AB - The mutation of Arginine273 to Histidine in the DNA binding domain of p53 is one of the most common mutations found in human cancer. Though R273H mutation retains wild-type conformation, the sequence-specific DNA binding is impaired and subsequently lack of transactivation function and the ability to suppress cell growth. CP-31398 can restore DNA binding activity to mutant p53 has shown by a chromatin immunoprecipitation assay but the underlying mechanism at atomistic level is not well understood. Our aim is to investigate theoretically the effect of R273H mutation on DNA binding and the mechanism of restoration of DNA binding by CP-31398, using docking and newly developed ultra accelerated quantum chemical molecular dynamics. Our results show that due to R273H mutation, p53 lost two hydrogen bonds with DNA at the binding site during interaction. CP-31398 helps to reestablish the lost hydrogen bond interactions at p53-DNA binding site, thus restore DNA binding activity and transcriptional activity. This will provide a deeper insight to structure-based drug designing.
KW - Docking
KW - Mutation
KW - P53-DNA interaction
KW - Quantum chemical molecular dynamics
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U2 - 10.1007/s00044-010-9514-z
DO - 10.1007/s00044-010-9514-z
M3 - Article
AN - SCOPUS:84861848845
VL - 21
SP - 239
EP - 244
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
SN - 1054-2523
IS - 2
ER -