3qi5 | pdb_00003qi5

Crystal structure of human alkyladenine DNA glycosylase in complex with 3,N4-ethenocystosine containing duplex DNA

spinqualitylabelsall models 3qi5, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qi5 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MN NonStd Res: EDC Gene: MPG, AAG, ANPG, MID1 (Homo sapiens) Activity: DNA-3-methyladenine glycosylase II, with EC number 3.2.2.21 Resources: FirstGlance, OCA, RCSB, PDBsum Function [3MG_HUMAN] Hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, and 7-methylguanine from the damaged DNA polymer formed by alkylation lesions. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA glycosylase

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