Molecular Modeling of O6-Methylguanine-DNA Methyltransferase Mutant Proteins Encoded by Single Nucleotide Polymorphisms

Journal Article · Sat Jan 01 04:00:00 EST 2005 · International Journal of Molecular Medicine

OSTI ID:932199

Schwarzl, S M ^[1]; Smith, Jeremy C ^[2]; Kaina, B ^[3]; Efferth, T ^[1]

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1. University of Heidelberg
2. ORNL
3. University of Mainz

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.

• Research Organization: Oak Ridge National Laboratory (ORNL)
• Sponsoring Organization: ORNL Program Development
• DOE Contract Number: AC05-00OR22725
• OSTI ID: 932199
• Journal Information: International Journal of Molecular Medicine, Journal Name: International Journal of Molecular Medicine Vol. 16
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
DNA
DNA REPAIR
MOLECULAR MODELS
MUTANTS
MUTATIONS
NUCLEOTIDES
PROTEINS