Structure of the error-prone DNA ligase of African swine fever virus identifies critical active site residues

• Published in: Nature communications 2019-01, Vol.10 (1), p.387-387, Article 387
• Main Authors: Chen, Yiqing, Liu, Hehua, Yang, Chun, Gao, Yanqing, Yu, Xiang, Chen, Xi, Cui, Ruixue, Zheng, Lina, Li, Suhua, Li, Xuhang, Ma, Jinbiao, Huang, Zhen, Li, Jixi, Gan, Jianhua
• Format: Article
• Language: English
• Subjects: 631/326/596; 631/337/1427/1429; 631/535/1266; African swine fever; African Swine Fever Virus - enzymology; African Swine Fever Virus - genetics; Asfarviridae; Base Sequence; Binding; Catalysis; Catalytic Domain; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA Ligases - chemistry; DNA Ligases - genetics; DNA Repair; DNA structure; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; Enzyme Assays; Fever; Genomes; Humanities and Social Sciences; Livestock; Models, Molecular; multidisciplinary; Mutagenesis; Protein Conformation; Protein Folding; Repair; Residues; Science; Science (multidisciplinary); Substrates; Swine; Viral Proteins - genetics; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08296-w

African swine fever virus (ASFV) is contagious and can cause highly lethal disease in pigs. ASFV DNA ligase (AsfvLIG) is one of the most error-prone ligases identified to date; it catalyzes DNA joining reaction during DNA repair process of ASFV and plays important roles in mutagenesis of the viral genome. Here, we report four AsfvLIG:DNA complex structures and demonstrate that AsfvLIG has a unique N-terminal domain (NTD) that plays critical roles in substrate binding and catalytic complex assembly. In combination with mutagenesis, in vitro binding and catalytic assays, our study reveals that four unique active site residues (Asn153 and Leu211 of the AD domain; Leu402 and Gln403 of the OB domain) are crucial for the catalytic efficiency of AsfvLIG. These unique structural features can serve as potential targets for small molecule design, which could impair genome repair in ASFV and help combat this virus in the future. The DNA ligase of African swine fever virus is one of the most error-prone ligases identified to date, but underlying molecular details are lacking. Here, Chen et al. report four AsfvLIG:DNA structures and identify a unique N-terminal domain and four unique active site residues that are crucial for its catalytic efficiency.