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Here we present a thermodynamic model that quantifies and links the major pathways by which mutations inactivate p53. We find that DBD possesses two unusual properties\u2014one of the highest zinc affinities of any eukaryotic protein and extreme instability in the absence of zinc\u2014which are predicted to poise p53 on the cusp of folding\/unfolding in the cell, with a major determinant being available zinc concentration. We analyze the 20 most common tumorigenic p53 mutations and find that 80% impair zinc affinity, thermodynamic stability, or both. Biophysical, cell-based, and murine xenograft experiments demonstrate that a synthetic zinc metallochaperone rescues not only mutations that decrease zinc affinity, but also mutations that destabilize DBD without impairing zinc binding. The results suggest that zinc metallochaperones have the capability to treat 120,500 patients annually in the U.S.<\/jats:p>","DOI":"10.7554\/elife.61487","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T12:02:49Z","timestamp":1606910569000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.61487","source":"Crossref","is-referenced-by-count":76,"title":["Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants"],"prefix":"10.7554","volume":"9","author":[{"given":"Adam R","family":"Blanden","sequence":"first","affiliation":[{"name":"Department of Neurology, SUNY Upstate Medical University, Syracuse, Syracuse, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yu","sequence":"additional","affiliation":[{"name":"Rutgers Cancer Institute of New Jersey, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0741-1550","authenticated-orcid":true,"given":"Alan J","family":"Blayney","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Demas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeung-Hoi","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[{"name":"Rutgers Cancer Institute of New Jersey, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Withers","sequence":"additional","affiliation":[{"name":"Rutgers Cancer Institute of New Jersey, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren R","family":"Carpizo","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Rochester School of Medicine and Dentistry and Wilmot Cancer Center, Rochester, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-9644","authenticated-orcid":true,"given":"Stewart N","family":"Loh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"bib1","volume-title":"ARUP Scientific Resource for Research and Education: BRCA Database","author":"ARUP Scientific Resource","year":"2020","unstructured":"ARUP Scientific Resource. 2020. 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