Identification of Inhibitors for the DEDDh Family of Exonucleases and a Unique Inhibition Mechanism by Crystal Structure Analysis of CRN-4 Bound with 2-Morpholin-4-ylethanesulfonate (MES)

Kuan Wei Huang, Kai Cheng Hsu, Lee Ya Chu, Jinn Moon Yang, Hanna S. Yuan, Yu Yuan Hsiao

研究成果: 雜誌貢獻文章

3 引文 斯高帕斯(Scopus)

摘要

The DEDDh family of exonucleases plays essential roles in DNA and RNA metabolism in all kingdoms of life. Several viral and human DEDDh exonucleases can serve as antiviral drug targets due to their critical roles in virus replication. Here using RNase T and CRN-4 as the model systems, we identify potential inhibitors for DEDDh exonucleases. We further show that two of the inhibitors, ATA and PV6R, indeed inhibit the exonuclease activity of the viral protein NP exonuclease of Lassa fever virus in vitro. Moreover, we determine the crystal structure of CRN-4 in complex with MES that reveals a unique inhibition mechanism by inducing the general base His179 to shift out of the active site. Our results not only provide the structural basis for the inhibition mechanism but also suggest potential lead inhibitors for the DEDDh exonucleases that may pave the way for designing nuclease inhibitors for biochemical and biomedical applications.
原文英語
頁(從 - 到)8019-8029
頁數11
期刊Journal of Medicinal Chemistry
59
發行號17
DOIs
出版狀態已發佈 - 九月 8 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Drug Discovery

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