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Targeting a dark excited state of HIV‐1 nucleocapsid by anti‐retroviral thioesters revealed by NMR

HIV‐1 nucleocapsid (NCp7) is a two Cys2HisCys zinc knuckle (N‐Zn and C‐Zn) protein that plays a key role in viral replication. Here we characterize NCp7 conformational dynamics 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 time scale 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‐S‐‐‐Zn or His421‐N2‐‐‐Zn) is hydrolysed. These findings explain why anti‐retroviral 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.

Authors:   Lalit Deshmukh, Vitali Tugarinov, Daniel H. Appella, G. Marius Clore
Journal:   Angewandte Chemie International Edition
Year:   2018
Pages:   n/a
DOI:   10.1002/anie.201713172
Publication date:   18-Jan-2018
Facts, background information, dossiers
  • drug design
  • Acylation
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