Targeted Covalent Inhibitors Allosterically Deactivate the DEDDh Lassa Fever Virus NP Exonuclease from Alternative Distal Sites.

ABSTRACT: For 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 exp

SUBMITTER: Huang KW 

PROVIDER: S-EPMC8715546 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature