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Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Nat+Struct+Mol+Biol 2017 ; 24 (2): 131-9 Nephropedia Template TP
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Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B #MMPMID27991903
Shi K; Carpenter M; Banerjee S; Shaban N; Kurahashi K; Salamango D; McCann J; Starrett G; Duffy J; Demir Ö; Amaro R; Harki D; Harris R; Aihara H
Nat Struct Mol Biol 2017[Feb]; 24 (2): 131-9 PMID27991903show ga
APOBEC-catalyzed cytosine-to-uracil deamination of single-stranded (ss)DNA has beneficial functions in immunity and detrimental roles in cancer. APOBEC enzymes have intrinsic dinucleotide specificities that impart hallmark mutation signatures. Despite numerous structures, mechanisms for global ssDNA recognition and local target sequence selection remain unclear. Here, we report crystal structures of human APOBEC3A and a chimera of human APOBEC3B and APOBEC3A bound to ssDNA at 3.1 and 1.7 angstroms resolution, respectively. These structures reveal a U-shaped DNA conformation, with the specificity-conferring ?1 thymine flipped out and the target cytosine inserted deep into the zinc-coordinating active site pocket. The ?1 thymine base fits between flexible loops in a groove that forms upon binding ssDNA, and it makes direct hydrogen bonds with the protein accounting for the strong 5?-TC preference. These studies explain both conserved and unique properties among APOBEC family members, and provide a basis for the rational design of inhibitors to impede the evolvability of viruses and tumors.