Title: 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)
Authors: Huang, Kuan-Wei
Hsu, Kai-Cheng
Chu, Lee-Ya
Yang, Jinn-Moon
Yuan, Hanna S.
Hsiao, Yu-Yuan
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
Institute of Molecular Medicine and Bioengineering
Issue Date: 8-Sep-2016
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 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.
URI: http://dx.doi.org/10.1021/acs.jmedchem.6b00794
ISSN: 0022-2623
DOI: 10.1021/acs.jmedchem.6b00794
Volume: 59
Issue: 17
Begin Page: 8019
End Page: 8029
Appears in Collections:Articles