6q0c

Publication Abstract from PubMed

The adenine glycosylase MutY selectively initiates repair of OG:A lesions and, by comparison, avoids G:A mispairs. The ability to distinguish these closely related substrates relies on the C-terminal domain of MutY which structurally resembles MutT. To understand the mechanism for substrate specificity, we crystallized MutY in complex with DNA containing G across from the high-affinity azaribose transition state analog. Our structure shows that G is accommodated by the OG site and highlights the role of a serine residue in OG versus G discrimination. The functional significance of Ser308 and its neighboring residues was evaluated by mutational analysis, revealing the critical importance of a beta-loop in the C-terminal domain for mutation suppression in cells, and biochemical performance in vitro. This loop comprising residues Phe307, Ser308, and His309 (Geobacillus stearothermophilus sequence positions) is conserved in MutY but absent in MutT and other DNA repair enzymes, and may therefore serve as a MutY-specific target exploitable by chemical biological probes.

Structural basis for finding OG lesions and avoiding undamaged G by the DNA glycosylase MutY.,Russelburg LP, O'Shea Murray VL, Demir M, Knutsen KR, Sehgal SL, Cao S, David SS, Horvath MP ACS Chem Biol. 2019 Dec 12. doi: 10.1021/acschembio.9b00639. PMID:31829624^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.