title: The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity.
abstract: In prokaryotes, two DNA glycosylases recognize and excise oxidized pyrimidines: endonuclease III (Nth) and endonuclease VIII (Nei). The oxidized purine 8-oxoguanine, on the other hand, is recognized by Fpg (also known as MutM), a glycosylase that belongs to the same family as Nei. The recent availability of the human genome sequence allowed the identification of three human homologs of Escherichia coli Nei. We report here the crystal structure of a human Nei-like (NEIL) enzyme, NEIL1. The structure of NEIL1 exhibits the same overall fold as E. coli Nei, albeit with an unexpected twist. Sequence alignments had predicted that NEIL1 would lack a zinc finger, and it was therefore expected to use a different DNA-binding motif instead. Our structure revealed that, to the contrary, NEIL1 contains a structural motif composed of two antiparallel beta-strands that mimics the antiparallel beta-hairpin zinc finger found in other Fpg/Nei family members but lacks the loops that harbor the zinc-binding residues and, therefore, does not coordinate zinc. This "zincless finger" appears to be required for NEIL1 activity, because mutating a very highly conserved arginine within this motif greatly reduces the glycosylase activity of the enzyme.
authors.affiliation: Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Stafford Hall, 95 Carrigan Drive, Burlington, VT 05405-0068, USA. sdoublie@uvm.edu
authors.forename: Sylvie
authors.initials: S
authors.lastname: Doublié
authors.forename: Viswanath
authors.initials: V
authors.lastname: Bandaru
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Bond
authors.forename: Susan S
authors.initials: SS
authors.lastname: Wallace
mesh_terms: D003461:Crystallography; D045647:DNA Glycosylases / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D016335:Zinc Fingers
chemical_list: D045647:DNA Glycosylases; C473634:NEIL1 protein, human