Molecular modeling of O6-methylguanine-DNA methyltransferase mutant proteins encoded by single nucleotide polymorphisms.
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) acts as a chemoprotectant and mediates resistance to alkylating anti-tumor agents. A number of MGMT single nucleotide polymorphisms (SNPs) have been described. We analyzed by molecular modeling the regions likely to be affected in the MGMT mutant proteins encoded by SNPs. Starting from the crystal structure of non-alkylated MGMT, molecular models of mutant proteins encoded by SNPs have been built. Most of the mutations were found to be located either within the DNA binding region (A121E, A121T, G132R, N123V) or in the vicinity of the active Cys145 (I143V, G160R). A further L84F mutant might affect Zn2+ binding. W65C was found to possibly be unstable.
Schwarzl
Sonja M
SM
Computational Molecular Biophysics, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Im Neuenheimer Feld 368, 69120 Heidelberg, Germany.
Smith
Jeremy C
JC
Kaina
Bernd
B
Efferth
Thomas
T
D000465:Algorithms; D001665:Binding Sites / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000737:chemistry* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017510:Protein Folding
D019853:O(6)-Methylguanine-DNA Methyltransferase