title: Combining structural and bioinformatics methods for the analysis of functionally important residues in DNA glycosylases.
abstract: An essential function of DNA glycosylases is the recognition and excision of damaged bases in DNA, thereby preserving genomic integrity. Lesion recognition is a multistep process, which is only partially revealed by structural analysis of the catalytically competent complex. The functional role of additional residues can be predicted by combining structural data with analysis of amino acid conservation. The following postulate underlies this approach: if a family or superfamily can be broken into subgroups with different substrate specificities, residues highly conserved between these subgroups represent those important for enzyme catalysis and structure maintenance while residues highly conserved within a subgroup but not between subgroups represent residues important for substrate specificity. We review the bioinformatics approach used for this quantitative analysis and describe its application to the Nth superfamily and Fpg family of DNA glycosylases. These results serve as a starting point in planning site-directed mutagenesis experiments to elucidate the functional role of similar and dissimilar residues in DNA repair and other proteins.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, 11794, USA.
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Zharkov
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D045647:DNA Glycosylases; D004260:DNA Repair; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009699:N-Glycosyl Hydrolases / Q000737:chemistry* / Q000502:physiology*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D004247:DNA; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases