Crystal structure of the Ilheus virus helicase: implications for enzyme function and drug design

Cell & Bioscience

Wen Cui¹  Wen-Ming Wang²  Yong-Mei Li³  Mei-Yue Wang³  Fang-Ying Jiang³  De-Ping Wang³  Wen Shu³  Xin Zhou³  Ji-Min Cao³ 

[1] Institute of Life Sciences, Chongqing Medical University;Institute of Molecular Science, Shanxi University;Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University;

关键词: Ilheus virus;    NS3 helicase;    Crystal structure;    ATP hydrolysis;    Molecular docking;   

DOI  :  10.1186/s13578-022-00777-8

来源: DOAJ

【 摘 要 】

Abstract Background The Ilheus virus (ILHV) is an encephalitis associated arthropod-borne flavivirus. It was first identified in Ilheus City in the northeast Brazil before spreading to a wider geographic range. No specific vaccines or drugs are currently available for the treatment of ILHV infections. The ILHV helicase, like other flavivirus helicases, possesses 5ʹ-triphosphatase activity. This allows it to perform ATP hydrolysis to generate energy as well as sustain double-stranded RNA’s unwinding during ILHV genome replication. Thus, ILHV helicase is an ideal target for inhibitor design. Results We determined the crystal structure of the ILHV helicase at 1.75-Å resolution. We then conducted molecular docking of ATP-Mn2+ to the ILHV helicase. Comparisons with related flavivirus helicases indicated that both the NTP and the RNA-ILHV helicase binding sites were conserved across intra-genus species. This suggested that ILHV helicase adopts an identical mode in recognizing ATP/Mn2+. However, the P-loop in the active site showed a distinctive conformation; reflecting a different local structural rearrangement. ILHV helicase enzymatic activity was also characterized. This was found to be relatively lower than that of the DENV, ZIKV, MVE, and ALSV helicases. Our structure-guided mutagenesis revealed that R26A, E110A, and Q280A greatly reduced the ATPase activities. Moreover, we docked two small molecule inhibitors of DENV helicase (ST-610 and suramin) to the ILHV helicase and found that these two molecules had the potential to inhibit the activity of ILHV helicase as well. Conclusion High-resolution ILHV helicase structural analysis demonstrates the key amino acids of ATPase activities and could be useful for the design of inhibitors targeting the helicase of ILHV.

【 授权许可】

Unknown