The effect of R249S carcinogenic and H168R-R249S suppressor mutations on p53-DNA interaction, a multi scale computational study.
In this study we have undertaken the theoretical analysis of the effect of R249S carcinogenic and H168R-R249S suppressor mutation at core domain of the tumor suppressor protein p53, on its natural interaction with DNA using a newly developed method. The results show that the carcinogenic mutation R249S affects the flexibility of L3 loop region in p53, inducing the loss of important hydrogen bonds observed at interaction in the wild-type with DNA, on the other hand the suppressor mutation H168R on the R249S assists in maintaining the wild-type like flexibility of the L3 region in p53 and thus recover the interaction terms lost in the carcinogenic mutation alone. The present study sets a new direction in the development of new drugs that may restore the interactions that lost as a consequence of the carcinogenic mutations in p53.
Rauf
Shah Md Abdur
SM
Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan. rauf_94@yahoo.com
Ismael
Mohamed
M
Sahu
Kamlesh Kumar
KK
Suzuki
Ai
A
Koyama
Michihisa
M
Tsuboi
Hideyuki
H
Hatakeyama
Nozomu
N
Endou
Akira
A
Takaba
Hiromitsu
H
Del Carpio
Carlos A
CA
Kubo
Momoji
M
Miyamoto
Akira
A
D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D008956:Models, Chemical; D008957:Models, Genetic; D009154:Mutation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA