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12-mer DNA structure of ExBIM bound to RNaseH -modified DDD12-mer DNA structure of ExBIM bound to RNaseH -modified DDD
Structural highlights
FunctionRNH1_ALKHC Endonuclease that specifically degrades the RNA of RNA-DNA hybrids.[1] Publication Abstract from PubMedO(6)-Methyl-2'-deoxyguanosine (O(6)-MeG) is one of the most common DNA lesions and arises as a consequence of both xenobiotic carcinogens and endogenous methylation by S-adenosylmethionine. O(6)-MeG frequently causes G-to-A mutations during DNA replication due to the misincorporation of dTTP and continued DNA synthesis. Efforts to detect DNA adducts such as O(6)-MeG, and to understand their impacts on DNA structure and function, have motivated the creation of nucleoside analogs with altered base moieties to afford a more favorable interaction with the adduct as compared to the unmodified nucleotide. Such analogs directed at O(6)-MeG include benzimidazolinone and benzimidazole nucleotides, as well as their extended pi surface analogs naphthimidazolinone and napthimidazole derivatives. These analogs form a more stable pair with O(6)-MeG than with G, most likely due to a combination of H-bonding and stacking. While extending the pi surface of the analogs enhances their performance as adduct-directed probes, the precise origins of the increased affinity between the synthetic analogs and O(6)-MeG remain unclear. To better understand relevant conformational and pairing properties, we used X-ray crystallography and analyzed the structures of the DNA duplexes with naphthimidazolinone inserted opposite G or O(6)-MeG. The structures reveal a complex interaction of the analog found either in an anti orientation and stacked inside the duplex, either above or below G or O(6)-MeG, or in a syn orientation and paired opposite G with formation of a single H-bond. The experimental structural data are consistent with the stabilizing effect of the synthetic analog observed in UV melting experiments and calculations and moreover reveal that the origin of these observations appears to be superior stacking between O(6)-MeG and the extended pi system of the synthetic probe. Conformation and Pairing Properties of an O(6)-Methyl-2'-deoxyguanosine-Directed Benzimidazole Nucleoside Analog in Duplex DNA.,Kellum AH Jr, Pallan PS, Nilforoushan A, Sturla SJ, Stone MP, Egli M Chem Res Toxicol. 2022 Aug 16. doi: 10.1021/acs.chemrestox.2c00165. PMID:35973057[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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