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Crystal structure of human thymine DNA glycosylase bound to a DNA substrate analog reveals the molecular basis of specificity and catalysis

Deamination of 5‐methylcytosine produces G·T mispairs, a mutagenic event that contributes to cancer and genetic disease. Thymine DNA glycosylase (TDG) recognizes these G·T lesions and excises thymine, and downstream base excision repair (BER) proteins restore a G·C pair. The task of excising a normal base from a mismatch, while avoiding the huge excess of undamaged DNA, presents a formidable challenge for a DNA glycosylase. TDG can also remove other damaged bases, including uracil and 5‐halogenated uracils, and has specificity for excising bases paired with guanine and located in a CpG context. We solved a crystal structure of TDG (catalytic domain) bound to DNA with a nonhydrolyzable substrate analog (2′‐fluoroarabino‐dU) flipped into its active site, providing a snapshot of the enzyme‐substrate complex in the absence of base‐sugar bond cleavage. TDG forms interactions with the uracil base that likely stabilize nucleotide flipping and promote specificity. The structure suggests that steric interactions with the methyl group of thymine could explain in part the much weaker binding observed for G·T relative to G·U substrates. Such interactions could potentially serve to minimize the aberrant excision of T from A·T pairs. Our structure indicates the mechanism of substrate recognition differs substantially for TDG enzymes relative to the closely related MUG enzymes. Supported by a grant from the NIH (GM‐072711).