3 years ago

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

G. Marius Clore, Lalit Deshmukh, Vitali Tugarinov, Daniel H. Appella
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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201713172

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