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Nucleic Acids Research 2005 33(15):5006-5016; doi:10.1093/nar/gki796
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Published online 6 September 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Structure of the uncomplexed DNA repair enzyme endonuclease VIII indicates significant interdomain flexibility

Gali Golan, Dmitry O. Zharkov1,2,3, Hadar Feinberg, Andrea S. Fernandes3, Elena I. Zaika3, Jadwiga H. Kycia4, Arthur P. Grollman3 and Gil Shoham*

Department of Inorganic Chemistry and the Laboratory for Structural Chemistry and Biology, The Hebrew University of Jerusalem Jerusalem 91904, Israel 1Institute of Chemical Biology and Fundamental Medicine, Siberian Division of the Russian Academy of Sciences Novosibirsk 630090, Russia 2Novosibirsk State University Novosibirsk 630090, Russia 3Laboratory of Chemical Biology, Department of Pharmacological Sciences, Stony Brook University Stony Brook, NY 11794-8651, USA 4Department of Biology, Brookhaven National Laboratories Upton, NY 11973, USA

*To whom correspondence should be addressed. Tel: +972 2 6585611; Fax: +972 2 6585319; Email: gil2{at}vms.huji.ac.il

Received May 24, 2005. Revised August 10, 2005. Accepted August 10, 2005.

Escherichia coli endonuclease VIII (Nei) excises oxidized pyrimidines from DNA. It shares significant sequence homology and similar mechanism with Fpg, a bacterial 8-oxoguanine glycosylase. The structure of a covalent Nei–DNA complex has been recently determined, revealing critical amino acid residues which are important for DNA binding and catalysis. Several Fpg structures have also been reported; however, analysis of structural dynamics of Fpg/Nei family proteins has been hindered by the lack of structures of uncomplexed and DNA-bound enzymes from the same source. We report a 2.8 Å resolution structure of free wild-type Nei and two structures of its inactive mutants, Nei-E2A (2.3 Å) and Nei-R252A (2.05 Å). All three structures are virtually identical, demonstrating that the mutations did not affect the overall conformation of the protein in its free state. The structures show a significant conformational change compared with the Nei structure in its complex with DNA, reflecting a ~50° rotation of the two main domains of the enzyme. Such interdomain flexibility has not been reported previously for any DNA glycosylase and may present the first evidence for a global DNA-induced conformational change in this class of enzymes. Several local but functionally relevant structural changes are also evident in other parts of the enzyme.

Protein Data Bank ID codes 1Q39, 1Q3C and 1Q3B


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