Targeting a Dark Excited State of HIV-1 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy.
Lalit DeshmukhVitali TugarinovDaniel H AppellaG Marius ClorePublished in: Angewandte Chemie (International ed. in English) (2018)
HIV-1 nucleocapsid (NCp7) is a two Cys2 HisCys zinc knuckle (N-Zn and C-Zn) protein that plays a key role in viral replication. NCp7 conformational dynamics is characterized by NMR relaxation dispersion and chemical exchange saturation transfer measurements. While the N-Zn knuckle is conformationally stable, the C-Zn knuckle interconverts on the millisecond timescale between the major state, in which the zinc is coordinated by three cysteines and a histidine, and two folded minor species (with populations around 1 %) in which one of the coordination bonds (Cys413-Sγ-Zn or His421-Nϵ2-Zn) is hydrolyzed. These findings explain why antiretroviral thioesters specifically disrupt the C-Zn knuckle by initial acylation of Cys413, and show that transient, sparsely-populated ("dark"), excited states of proteins can present effective targets for rational drug design.
Keyphrases
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- coronavirus disease