7T7H
Crystal structure of Vaccinia Virus decapping enzyme D9 in complex with inhibitor CP100356
Summary for 7T7H
| Entry DOI | 10.2210/pdb7t7h/pdb |
| Descriptor | DNA repair NTP-phosphohydrolase, SODIUM ION, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-6,7-dimethoxyquinazolin-2-amine, ... (4 entities in total) |
| Functional Keywords | decapping enzyme, nudix, inhibitor, viral protein-viral protein inhibitor complex, viral protein/viral protein inhibitor |
| Biological source | Vaccinia virus Western Reserve |
| Total number of polymer chains | 2 |
| Total formula weight | 53371.42 |
| Authors | Peters, J.K.,Gross, J.D. (deposition date: 2021-12-15, release date: 2022-06-15, Last modification date: 2023-10-18) |
| Primary citation | Bednarczyk, M.,Peters, J.K.,Kasprzyk, R.,Starek, J.,Warminski, M.,Spiewla, T.,Mugridge, J.S.,Gross, J.D.,Jemielity, J.,Kowalska, J. Fluorescence-Based Activity Screening Assay Reveals Small Molecule Inhibitors of Vaccinia Virus mRNA Decapping Enzyme D9. Acs Chem.Biol., 17:1460-1471, 2022 Cited by PubMed Abstract: Vaccinia virus (VACV) represents a family of poxviruses, which possess their own decapping machinery as a part of their strategy to eliminate host mRNAs and evade the innate immune response. D9 is one of the two encoded VACV decapping enzymes that is responsible for cap removal from the 5' end of both host mRNA transcripts and viral double-stranded RNAs. Little is known about the structural requirements for D9 inhibition by small molecules. Here, we identified a minimal D9 substrate and used it to develop a real-time fluorescence assay for inhibitor discovery and characterization. We screened a panel of nucleotide-derived substrate analogues and pharmacologically active candidates to identify several compounds with nano- and low micromolar IC values. mGpppCHp was the most potent nucleotide inhibitor (IC ∼ 0.08 μM), and seliciclib and CP-100356 were the most potent drug-like compounds (IC 0.57 and 2.7 μM, respectively). The hits identified through screening inhibited D9-catalyzed decapping of 26 nt RNA substrates but were not active toward VACV D10 or human decapping enzyme, Dcp1/2. The inhibition mode for one of the compounds (CP-100356) was elucidated based on the X-ray cocrystal structure, opening the possibility for structure-based design of novel D9 inhibitors and binding probes. PubMed: 35576528DOI: 10.1021/acschembio.2c00049 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78000262178 Å) |
Structure validation
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