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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).

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Huang KW,Hsu KC,Chu LY,Yang JM,Yuan HS,Hsiao YY

doi

10.1021/acs.jmedchem.6b00794

subject

Has Abstract

pub_date

2016-09-08 00:00:00

pages

8019-29

issue

17

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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