Targeting a Dark Excited State of HIV‐1 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy. (2nd February 2018)

• Record Type: Journal Article
• Authors: Deshmukh, Lalit; Tugarinov, Vitali; Appella, Daniel H.; Clore, G. Marius
• Is Part Of: Angewandte Chemie. Volume 130:Number 10(2018)
• Page Start: 2717
• Page End: 2721
• Publication Date: 2018-02-02
• Subjects: Antiretrovirale Wirkstoffe -- HIV-1-Nucleocapsid -- Konformationswechsel -- Relaxationsdispersion -- Zink; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201713172
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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‐N ϵ 2‐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.