Targeting a dark excited state of HIV-1 nucleocapsid by anti-retroviral thioesters revealed by NMR.
Related Articles Targeting a dark excited state of HIV-1 nucleocapsid by anti-retroviral thioesters revealed by NMR.
Angew Chem Int Ed Engl. 2018 Jan 18;:
Authors: Deshmukh L, Tugarinov V, Appella DH, Clore GM
Abstract
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.
PMID: 29345807 [PubMed - as supplied by publisher]
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