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NCp7 conformational dynamics is characterized by NMR relaxation dispersion and chemical exchange saturation transfer measurements. While the N\u2010Zn knuckle is conformationally stable, the C\u2010Zn 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\u2009%) in which one of the coordination bonds (Cys413\u2010S\u03b3\u2010Zn or His421\u2010N<jats:italic>\u03f5<\/jats:italic>2\u2010Zn) is hydrolyzed. These findings explain why antiretroviral thioesters specifically disrupt the C\u2010Zn knuckle by initial acylation of Cys413, and show that transient, sparsely\u2010populated (\u201cdark\u201d), excited states of proteins can present effective targets for rational drug design.<\/jats:p>","DOI":"10.1002\/anie.201713172","type":"journal-article","created":{"date-parts":[[2018,1,18]],"date-time":"2018-01-18T17:14:11Z","timestamp":1516295651000},"page":"2687-2691","source":"Crossref","is-referenced-by-count":34,"title":["Targeting a Dark Excited State of HIV\u20101 Nucleocapsid by Antiretroviral Thioesters Revealed by NMR Spectroscopy"],"prefix":"10.1002","volume":"57","author":[{"given":"Lalit","family":"Deshmukh","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases  Bethesda MD 20892-0520 USA"},{"name":"Present address: Department of Chemistry and Biochemistry University of California, San Diego  La Jolla CA 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vitali","family":"Tugarinov","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases  Bethesda MD 20892-0520 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Appella","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic Chemistry National Institute of Diabetes and Digestive and Kidney Diseases  Bethesda MD 20892-0830 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3809-1027","authenticated-orcid":false,"given":"G. 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