Published on None in volume (2019) Chem Asian J 14: 2235-2241 .

PubMed ID: 31116511

DOI: 10.1002/asia.201900480

Abstract:

Human APOBEC3G (A3G) inhibits the replication of human immunodeficiency virus-1 by deaminating cytidine at the 3'-end in the target motif 5'-CCC-3' in viral cDNA during reverse transcription. It in vitro deaminates two consecutive cytidines in a 3'->5' order. Although a crystal structure of the A3G catalytic domain (A3G-CD2) with DNA was reported, it is unknown why residues involved in enzymatic reaction are distributed widely. Here, we introduced an iodine atom into the C-5 position of cytidine (dC 6 I ) in DNA 5'-ATTC 4 C 5 C 6 I A 7 ATT-3' (TCCC 6 I ). It switches the deamination sequence preference from CCC to TCC, although small dC 6 I deamination was observed. Solution structures of A3G-CD2 in complexes with products DNA TCUC 6 I and TCUU 6 I indicate that the substrate DNA binds A3G-CD2 in TCC and CCC modes. The dC 6 deamination correlates with the 4 th base type. The CCC mode favours dC 6 deamination, while the TCC mode results in dC 5 deamination. These studies present an extensive basis to design inhibitors to impede viral evolvability.