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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8019-8029
Number of pages11
JournalJournal of Medicinal Chemistry
Volume59
Issue number17
DOIs
Publication statusPublished - Sep 8 2016

Fingerprint

Exonucleases
Lassa Fever
Lassa virus
Viral Proteins
Virus Replication
Antiviral Agents
Catalytic Domain
RNA
DNA

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Drug Discovery

Cite this

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

In: Journal of Medicinal Chemistry, Vol. 59, No. 17, 08.09.2016, p. 8019-8029.

Research output: Contribution to journalArticle

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AU - Hsu, Kai Cheng

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AU - Hsiao, Yu Yuan

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AB - 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.

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