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.
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Targeted Covalent Inhibitors Allosterically Deactivate the DEDDh Lassa Fever Virus NP Exonuclease from Alternative Distal Sites.
JACS Au
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Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan.
Article Synopsis
- This study identifies PCMPS and PCMB as targeted covalent inhibitors of DEDDh exonucleases, which are significant for cancer and antiviral therapies.
- The research utilizes X-ray crystallography, binding assays, and molecular dynamics simulations to understand the binding sites and mechanisms of these compounds, particularly focusing on Cys409 and Cys461 in the Lassa fever virus NP exonuclease.
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State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science and College of Life Sciences, Nankai University, 38 Tongyan Road, Tianjin 300350, People's Republic of China.
Oligoribonuclease (Orn), a member of the DEDDh superfamily, can hydrolyse 2-5 nt nanoRNAs to mononucleotides. It is involved in maintaining the intracellular levels of RNA, c-di-GMP signalling and transcription initiation in many bacterial species. Here, the crystal structure of Orn from Vibrio cholerae O1 El Tor (VcOrn) is reported at a resolution of 1.
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We report a molecular-docking and virtual-screening-based identification and characterization of interactions of lead molecules with exoribonuclease (ExoN) enzyme in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From previously identified DEDDh/DEEDh subfamily nuclease inhibitors, our results revealed strong binding of pontacyl violet 6R (PV6R) at the catalytic active site of ExoN. The binding was found to be stabilized two hydrogen bonds and hydrophobic interactions.
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Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30068, Taiwan, ROC.
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.
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