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Targeting a Dark Excited State of HIV‐1 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy
Author(s) -
Deshmukh Lalit,
Tugarinov Vitali,
Appella Daniel H.,
Clore G. Marius
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201713172
Subject(s) - chemistry , zinc , excited state , nuclear magnetic resonance spectroscopy , zinc finger , human immunodeficiency virus (hiv) , crystallography , histidine , stereochemistry , virology , amino acid , biochemistry , biology , physics , gene , atomic physics , organic chemistry , transcription factor
HIV‐1 nucleocapsid (NCp7) is a two Cys 2 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.