TY - JOUR
T1 - Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA
T2 - Mechanisms for nucleotide flipping and base excision
AU - Lau, Albert Y.
AU - Schärer, Orlando D.
AU - Samson, Leona
AU - Verdine, Gregory L.
AU - Ellenberger, Tom
N1 - Funding Information:
We thank Robert Sweet for his expert assistance at beamline X12C, National Synchrotron Light Source (Upton, NY), and Sylvie Doublié, Thomas Hollis, and Dane Walther for helping with X-ray data collection. We appreciate the advice and encouragement of the Ellenberger, Verdine, and Samson research groups. This work was supported by grants from the National Institutes of Health (L. S., G. L. V., T. E.) and the Lucille P. Markey Charitable Trust (T. E.). L. S. is a Burroughs Wellcome Toxicology Scholar. We gratefully acknowledge the support of the Harvard Center for Structural Biology and the Giovanni Armenise-Harvard Foundation for Advanced Scientific Research.
PY - 1998/10/16
Y1 - 1998/10/16
N2 - DNA N-glycosylases are base excision-repair proteins that locate and cleave damaged bases from DNA as the first step in restoring the genetic blueprint. The human enzyme 3-methyladenine DNA glycosylase removes a diverse group of damaged bases from DNA, including cytotoxic and mutagenic alkylation adducts of purines. We report the crystal structure of human 3-methyladenine DNA glycosylase complexed to a mechanism-based pyrrolidine inhibitor. The enzyme has intercalated into the minor groove of DNA, causing the abasic pyrrolidine nucleotide to flip into the enzyme active site, where a bound water is poised for nucleophilic attack. The structure shows an elegant means of exposing a nucleotide for base excision as well as a network of residues that could catalyze the in-line displacement of a damaged base from the phosphodeoxyribose backbone.
AB - DNA N-glycosylases are base excision-repair proteins that locate and cleave damaged bases from DNA as the first step in restoring the genetic blueprint. The human enzyme 3-methyladenine DNA glycosylase removes a diverse group of damaged bases from DNA, including cytotoxic and mutagenic alkylation adducts of purines. We report the crystal structure of human 3-methyladenine DNA glycosylase complexed to a mechanism-based pyrrolidine inhibitor. The enzyme has intercalated into the minor groove of DNA, causing the abasic pyrrolidine nucleotide to flip into the enzyme active site, where a bound water is poised for nucleophilic attack. The structure shows an elegant means of exposing a nucleotide for base excision as well as a network of residues that could catalyze the in-line displacement of a damaged base from the phosphodeoxyribose backbone.
UR - http://www.scopus.com/inward/record.url?scp=0032538337&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(00)81755-9
DO - 10.1016/S0092-8674(00)81755-9
M3 - Article
C2 - 9790531
AN - SCOPUS:0032538337
SN - 0092-8674
VL - 95
SP - 249
EP - 258
JO - Cell
JF - Cell
IS - 2
ER -