7v38
From Proteopedia
Crystal structure of NP exonuclease-PCMPS complex
Structural highlights
FunctionNCAP_LASSJ Encapsidates the genome, protecting it from nucleases. The encapsidated genomic RNA is termed the nucleocapsid (NC). Serves as template for viral transcription and replication. The increased presence of protein N in host cell does not seem to trigger the switch from transcription to replication as observed in other negative strain RNA viruses. Disables the host innate defense by interfering with beta interferon (IFN-beta) production. Strongly inhibits the nuclear translocation of IRF3, a protein involved in IFN activation pathway. Also inhibits the activation of IFN-beta and IRF3-dependent promoters (By similarity). Publication Abstract from PubMedFor using targeted covalent inhibitors (TCIs) as anticancer and antiviral drugs, we establish that the model compounds PCMPS (p-chloromercuriphenyl sulfate) and PCMB (p-chloromercuribenzoate) are inhibitors of the DEDDh family of exonucleases. The underlying mechanism is analyzed by X-ray crystallography, activity/nucleic acid-binding assays, and all-atom molecular dynamics (MD) simulations. The first TCI-complexed structures of a DEDDh enzyme, the Lassa fever virus NP exonuclease (NPexo), are resolved to elucidate that the Cys409 binding site is away from the active site and the RNA-binding lid. The NPexo C409A structures indicate Cys461 as the alternative distal site for obstructing the equally active mutant. All-atom MD simulations of the wild type and mutant NPexos in explicit solvent uncover an allosteric inhibition mechanism that the local perturbation induced by PCMPS sulfonate propagates to impact the RNA-binding lid conformation. Binding assay studies confirm that PCMPS does affect the RNA binding of NPexo. The predicted relative potency between PCMPS and PCMB is also in line with experiments. The structural data and inhibition mechanism established in this work provide an important molecular basis for the drug development of TCIs. Targeted Covalent Inhibitors Allosterically Deactivate the DEDDh Lassa Fever Virus NP Exonuclease from Alternative Distal Sites.,Huang KW, Chen JW, Hua TY, Chu YY, Chiu TY, Liu JY, Tu CI, Hsu KC, Kao YT, Chu JW, Hsiao YY JACS Au. 2021 Nov 16;1(12):2315-2327. doi: 10.1021/jacsau.1c00420. eCollection, 2021 Dec 27. PMID:34977900[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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