3qi5

Publication Abstract from PubMed

Reactive oxygen and nitrogen species, generated by neutrophils and macrophages in chronically inflamed tissues, readily damage DNA, producing a variety of potentially genotoxic etheno base lesions; such inflammation-related DNA damage is now known to contribute to carcinogenesis. While the human alkyladenine DNA glycosylase (AAG) can specifically bind DNA containing either 1,N(6)-ethenoadenine (epsilonA) lesions, or 3,N(4)- ethenocytosine (epsilonC) lesions, it can only excise epsilonA lesions. AAG binds very tightly to DNA containing epsilonC lesions, forming an abortive protein-DNA complex; such binding not only shields epsilonC from repair by other enzymes, but also inhibits AAG from acting on other DNA lesions. To understand the structural basis for inhibition, we have characterized the binding of AAG to DNA containing epsilonC lesions and have solved a crystal structure of AAG bound to a DNA duplex containing the epsilonC lesion. This study provides the first structure of a DNA glycosylase in complex with an inhibitory base lesion that is induced endogenously and that is also induced upon exposure to environmental agents such as vinyl chloride. We identify the primary cause of inhibition as a failure to activate the nucleotide base as an efficient leaving group, and demonstrate that the higher binding affinity of AAG for epsilonC versus epsilonA is achieved through formation of an additional hydrogen bond between Asn169 in the active site pocket and the O(2) of epsilonC. This structure provides the basis for the design of AAG inhibitors currently being sought as an adjuvant for cancer chemotherapy.

Structural basis for the inhibition of human alkyladenine DNA glycosylase (AAG) by 3,N4-ethenocytosine containing DNA.,Lingaraju GM, Davis CA, Setser JW, Samson LD, Drennan CL J Biol Chem. 2011 Feb 24. PMID:21349833^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.