Solution Structure and Base Perturbation Studies Reveal a Novel Mode of Alkylated Base Recognition by 3-Methyladenine DNA Glycosylase I

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Abstract

The specific recognition mechanisms of DNA repair glycosylases that remove cationic alkylpurine bases in DNA are not well understood partly due to the absence of structures of these enzymes with their cognate bases. Here we report the solution structure of 3-methyladenine DNA glycosylase I (TAG) in complex with its 3-methyladenine (3-MeA) cognate base, and we have used chemical perturbation of the base in combination with mutagenesis of the enzyme to evaluate the role of hydrogen bonding and π-cation interactions in alkylated base recognition by this DNA repair enzyme. We find that TAG uses hydrogen bonding with heteroatoms on the base, van der Waals interactions with the 3-Me group, and conventional π-π stacking with a conserved Trp side chain to selectively bind neutral 3-MeA over the cationic form of the base. Discrimination against binding of the normal base adenine is derived from direct sensing of the 3-methyl group, leading to an induced-fit conformational change that engulfs the base in a box defined by five aromatic side chains. These findings indicate that base specific recognition by TAG does not involve strong π-cation interactions, and suggest a novel mechanism for alkylated base recognition and removal.

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Cao, C., Kwon, K., Jiang, Y. L., Drohat, A. C., & Stivers, J. T. (2003). Solution Structure and Base Perturbation Studies Reveal a Novel Mode of Alkylated Base Recognition by 3-Methyladenine DNA Glycosylase I. Journal of Biological Chemistry, 278(48), 48012–48020. https://doi.org/10.1074/jbc.M307500200

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