5DK5

Crystal structure of CRN-4-MES complex

Summary for 5DK5

• Entry DOI: 10.2210/pdb5dk5/pdb
• Descriptor: Cell death-related nuclease 4, ZINC ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (6 entities in total)
• Functional Keywords: deddh exonuclease, inhibitor, complex structure, dnase, rnase, hydrolase
• Biological source: Caenorhabditis elegans
• Total number of polymer chains: 2
• Total formula weight: 72175.82

Authors

Hsiao, Y.-Y.,Yuan, H.S. (deposition date: 2015-09-03, release date: 2016-08-24, Last modification date: 2023-11-08)

Primary citation

Huang, K.-W.,Hsu, K.-C.,Chu, L.-Y.,Yang, J.-M.,Yuan, H.S.,Hsiao, Y.-Y.
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)
J.Med.Chem., 59:8019-8029, 2016

PubMed 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.

PubMed: 27529560
DOI: 10.1021/acs.jmedchem.6b00794

Experimental method

X-RAY DIFFRACTION (2.1 Å)