The complex structures of ALKBH2 mutants cross-linked to dsDNA reveal the conformational swing of β-hairpin

Mammalian AlkB homologue 2 (ALKBH2) is the primary housekeeping DNA demethylase, effectively repairing endogenously formed methylated lesions in double-stranded DNA. Our previous studies demonstrated that a hydrophobic beta-hairpin motif of ALKBH2 could play crucial roles in base-pair stability interrogation and damaged base flipping. Using chemical cross-linking strategy, we obtained two crystal structures of human ALKBH2 mutant bound to duplex DNA. The structural analysis suggests that the beta-hairpin motif is flexible in conformation and is likely to slide along the DNA duplex in local regions to search for damaged base. This study provides a new mechanistic insight into DNA damage detection by ALKBH2.