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)
Open Access
- 29 August 2016
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 59 (17), 8019-8029
- https://doi.org/10.1021/acs.jmedchem.6b00794
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.Keywords
Funding Information
- Academia Sinica
- Ministry of Science and Technology, Taiwan (MOST103-2311-B-009 -001 -MY3)
This publication has 64 references indexed in Scilit:
- Crystal structures of Escherichia coli exonuclease I in complex with single-stranded DNA provide insights into the mechanism of processive digestionNucleic Acids Research, 2013
- Structural Basis for the dsRNA Specificity of the Lassa Virus NP ExonucleasePLOS ONE, 2012
- How an exonuclease decides where to stop in trimming of nucleic acids: crystal structures of RNase T–product complexesNucleic Acids Research, 2012
- Nucleases: diversity of structure, function and mechanismQuarterly Reviews of Biophysics, 2010
- Crystal Structure of CRN-4: Implications for Domain Function in Apoptotic DNA DegradationMolecular and Cellular Biology, 2009
- A novel mutation of the WRN gene in a Chinese patient with Werner syndromeClinical and Experimental Dermatology, 2008
- Genetic and biochemical characterization ofDrosophilaSnipper: A promiscuous member of the metazoan 3′hExo/ERI-1 family of 3′ to 5′ exonucleasesRNA, 2006
- WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processingNature Structural & Molecular Biology, 2006
- Crystal structure of human ISG20, an interferon‐induced antiviral ribonucleaseFEBS Letters, 2004
- Exoribonuclease superfamilies: structural analysis and phylogenetic distributionNucleic Acids Research, 2001