Molecular simulations reveal a common binding mode for glycosylase binding of oxidatively damaged DNA lesions.
Cellular DNA is constantly exposed to oxidative stress from both exogenous and endogenous sources, creating lesions that lead to aging related diseases, including cancer. 8-Oxo-guanine (8OG) is one of the most common forms of oxidative DNA damage, and failure to repair this lesion results in G:C to T:A transversion. Another common lesion, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapydG), shares the same precursor as 8OG. In Escherichia coli, both lesions are recognized and excised by the DNA glycosylase Fpg. X-ray crystallographic studies have shown that FapydG and 8OG adopt different conformations in the active site of Fpg. Our simulations suggest that the different binding modes observed for 8OG and FapydG arise directly from response to the nonconserved E77 present in the thermophilic Fpg sequences used for the crystallography experiments. In simulations with consensus S77, these lesions adopt very similar binding modes.
Song
Kun
K
Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, USA.
Kelso
Catherine
C
de los Santos
Carlos
C
Grollman
Arthur P
AP
Simmerling
Carlos
C
D001483:Base Sequence; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D018384:Oxidative Stress
D004247:DNA; D045647:DNA Glycosylases