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J. Biol. Chem., Vol. 279, Issue 42, 44074-44083, October 15, 2004

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Structural Basis for the Recognition of the FapydG Lesion (2,6-Diamino-4-hydroxy-5-formamidopyrimidine) by Formamidopyrimidine-DNA Glycosylase^*

Franck Coste, Matthias Ober, Thomas Carell¶, Serge Boiteux||, Charles Zelwer, and Bertrand Castaing**

From the Centre de Biophysique Moléculaire, UPR4301, CNRS, rue Charles Sadron, 45071 Orléans Cedex 02, France, Department of Chemistry, Ludwig-Maximilians University Munich, 5-13, D-81377 Munich, Germany, and ^||Radiobiologie Moléculaire et Cellulaire, UMR217, CNRS-Commissariat à l'Energie Atomique, BP6, 92265 Fontenay-Aux-Roses, France

Formamidopyrimidine-DNA glycosylase (Fpg) is a DNA repair enzyme that excises oxidized purines such as 7,8-dihydro-8-oxoguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) from damaged DNA. Here, we report the crystal structure of the Fpg protein from Lactococcus lactis (LlFpg) bound to a carbocyclic FapydG (cFapydG)-containing DNA. The structure reveals that Fpg stabilizes the cFapydG nucleoside into an extrahelical conformation inside its substrate binding pocket. In contrast to the recognition of the 8-oxodG lesion, which is bound with the glycosidic bond in a syn conformation, the cFapydG lesion displays in the complex an anti conformation. Furthermore, Fpg establishes interactions with all the functional groups of the FapyG base lesion, which can be classified in two categories: (i) those specifying a purine-derived lesion (here a guanine) involved in the Watson-Crick face recognition of the lesion and probably contributing to an optimal orientation of the pyrimidine ring moiety in the binding pocket and (ii) those specifying the imidazole ring-opened moiety of FapyG and probably participating also in the rotameric selection of the FapydG nucleobase. These interactions involve strictly conserved Fpg residues and structural water molecules mediated interactions. The significant differences between the Fpg recognition modes of 8-oxodG and FapydG provide new insights into the Fpg substrate specificity.

Received for publication, May 27, 2004 , and in revised form, July 9, 2004.

The atomic coordinates and structure factors (code 1TDZ) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The abbreviations used are: 8-oxoG, 7,8-dihydro-8-oxoguanine; Fapy, formamidopyrimidine; FapyG, guanine with the imidazole ring opened; Fpg, formamidopyrimidine-DNA glycosylase; AP, abasic (apurinic/apyrimidic); FapydG, guanosine with the imidazole ring opened; 8-oxodG, 8-oxodeoxyguanosine; hOgg1, human 8-oxoguanine-DNA glycosylase 1; AFB1, aflatoxine B1; Z, oxazolone.

^* This work was supported by the Centre National de la Recherche Scientique (CNRS) and by Electricité de France (EDF). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence may be addressed. E-mail: thomas.carell{at}cup.uni-muenchen.de.

^** To whom correspondence may be addressed. E-mail: castaing{at}cnrs-orleans.fr.

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