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The formation of Hg(Cys)<jats:sub><jats:italic>x<\/jats:italic><\/jats:sub> cores in catalytic and structural protein centers mediates mercury's toxic effects and ultimately leads to cellular damage. Multiple studies have revealed distinct Hg<jats:sup>II<\/jats:sup>\u2010thiolate coordination preferences, among which linear Hg<jats:sup>II<\/jats:sup> complexes are the most commonly observed in solution at physiological pH. Trigonal or tetrahedral geometries are formed at basic pH or in tight intraprotein Cys\u2010rich metal sites. So far, no interprotein tetrahedral Hg<jats:sup>II<\/jats:sup> complex formed at neutral pH has been reported. Rad50 protein is a part of the multiprotein MRN complex, a major player in DNA damage\u2010repair processes. Its central region consists of a conserved CXXC motif that enables dimerization of two Rad50 molecules by coordinating Zn<jats:sup>II<\/jats:sup>. Dimerized motifs form a unique interprotein zinc hook domain (Hk) that is critical for the biological activity of the MRN. Using a series of length\u2010differentiated peptide models of the <jats:italic>Pyrococcus furiosus<\/jats:italic> zinc hook domain, we investigated its interaction with Hg<jats:sup>II<\/jats:sup>. Using UV\u2010Vis, CD, PAC, and <jats:sup>199<\/jats:sup>Hg\u2005NMR spectroscopies as well as anisotropy decay, we discovered that all Rad50 fragments preferentially form homodimeric Hg(Hk)<jats:sub>2<\/jats:sub> species with a distorted tetrahedral HgS<jats:sub>4<\/jats:sub> coordination environment at physiological pH; this is the first example of an interprotein mercury site displaying tetrahedral geometry in solution. At higher Hg<jats:sup>II<\/jats:sup> content, monomeric HgHk complexes with linear geometry are formed. The Hg(Cys)<jats:sub>4<\/jats:sub> core of Rad50 is extremely stable and does not compete with cyanides, NAC, or DTT. Applying ITC, we found that the stability constant of the Rad50 Hg(Hk)<jats:sub>2<\/jats:sub> complex is approximately three orders of magnitude higher than those of the strongest Hg<jats:sup>II<\/jats:sup> complexes known to date.<\/jats:p>","DOI":"10.1002\/chem.202202738","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T07:01:05Z","timestamp":1665558065000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An Extremely Stable Interprotein Tetrahedral Hg(Cys)<sub>4<\/sub> Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5721-8380","authenticated-orcid":false,"given":"Marek","family":"\u0141uczkowski","sequence":"first","affiliation":[{"name":"Department of Chemical Biology Faculty of Biotechnology University of Wroc\u0142aw  Joliot-Curie 14a 50-383 Wroc\u0142aw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-3302","authenticated-orcid":false,"given":"Micha\u0142","family":"Padjasek","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology Faculty of Biotechnology University of Wroc\u0142aw  Joliot-Curie 14a 50-383 Wroc\u0142aw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0496-9519","authenticated-orcid":false,"given":"J\u00f3zef","family":"Ba Tran","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology Faculty of Biotechnology University of Wroc\u0142aw  Joliot-Curie 14a 50-383 Wroc\u0142aw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1823-3035","authenticated-orcid":false,"given":"Lars","family":"Hemmingsen","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Copenhagen  Universitetsparken 5 2100 K\u00f8benhavn \u00d8 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-5393","authenticated-orcid":false,"given":"Olga","family":"Kerber","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology Faculty of Biotechnology University of Wroc\u0142aw  Joliot-Curie 14a 50-383 Wroc\u0142aw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1365-8624","authenticated-orcid":false,"given":"Jelena","family":"Habjani\u010d","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Zurich  Winterthurerstrasse 190 8057 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3102-6329","authenticated-orcid":false,"given":"Eva","family":"Freisinger","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Zurich  Winterthurerstrasse 190 8057 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Kr\u0119\u017cel","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology Faculty of Biotechnology University of Wroc\u0142aw  Joliot-Curie 14a 50-383 Wroc\u0142aw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"e_1_2_8_1_1","volume-title":"Encyclopedia of Inorganic and Bioinorganic Chemistry","author":"Bebout D. 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