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)

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 po...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-09, Vol.59 (17), p.8019-8029
Main Authors: Huang, Kuan-Wei, Hsu, Kai-Cheng, Chu, Lee-Ya, Yang, Jinn-Moon, Yuan, Hanna S, Hsiao, Yu-Yuan
Format: Article
Language:English
Subjects:
Alkanesulfonic Acids - chemistry
Caenorhabditis elegans Proteins - antagonists & inhibitors
Caenorhabditis elegans Proteins - chemistry
Catalytic Domain
Crystallography, X-Ray
DNA, Single-Stranded - chemistry
Endodeoxyribonucleases - antagonists & inhibitors
Endodeoxyribonucleases - chemistry
Exonucleases - antagonists & inhibitors
Exonucleases - chemistry
Exoribonucleases - antagonists & inhibitors
Exoribonucleases - chemistry
Lassa virus - enzymology
Molecular Docking Simulation
Molecular Structure
Morpholines - chemistry
RNA - chemistry
Viral Proteins - antagonists & inhibitors
Viral Proteins - chemistry
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00794