期刊
ACS CHEMICAL BIOLOGY
卷 15, 期 1, 页码 93-102出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.9b00639
关键词
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资金
- NSF Chemistry of Life Processes (CLP) awards [1610721, 1608934]
- NIH/NCI [CA067985]
- NIH predoctoral training fellowships [GM08537, CA093247]
- DOE Office of Biological and Environmental Research
- National Institutes of Health Project ALS-ENABLE [P30 GM124169]
- high-end instrumentation grant [S10OD018483]
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 analogue. 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.
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