{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:06:20Z","timestamp":1789477580628,"version":"build-2803163510"},"reference-count":27,"publisher":"American Chemical Society (ACS)","issue":"18","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/na","name":"Flare Therapeutics, Inc.","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We present evidence of previously unrecognized allosteric connectivity across the TP53 DNA-binding domain (DBD). Specifically, we have found evidence of an explicit influence on the Zn2+-binding site from the region surrounding the hotspot Y220C mutation. This allosteric connectivity is intertwined with a temperature-dependent destabilization of Zn2+ binding in both the WT and the Y220C DBDs. Our studies indicate that the Y220C mutation exacerbates this temperature-dependent destabilization of Zn2+ binding to result in overall destabilization of the Y220C variant. We provide detailed thermodynamic evidence that Rezatapopt, a small molecule reactivator of the Y220C DBD, engages Y220C through two thermodynamically distinct binding mechanisms and restores WT-level Zn2+-affinity to this oncogenic variant. A series of thermodynamic models describing the WT and Y220C conformational landscapes as well as the Rezatapopt binding mechanisms are proposed.<\/jats:p>","DOI":"10.1021\/acs.biochem.6c00068","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:08:45Z","timestamp":1788437325000},"page":"2851-2864","source":"Crossref","is-referenced-by-count":0,"title":["Thermodynamic\nInsights into the WT and Y220C TP53\nDBDs Reveal that the Oncogenic Y220C Variant is a Loss-of-Function\nMutation for Zn2+-Binding at Physiological Temperature"],"prefix":"10.1021","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1389-5819","authenticated-orcid":true,"given":"Jacob I.","family":"Stuckey","sequence":"first","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Vivat","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4995-9111","authenticated-orcid":true,"given":"Bradley M.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Van Andel Institute , , ,","place":["Grand Rapids, Michigan, United States, 49503"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy W.","family":"Setser","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Li","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia M.","family":"Cremers","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Peterle","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Engen","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Wales","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6159-1460","authenticated-orcid":true,"given":"Rainer","family":"Wilcken","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin B.","family":"Rohan","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregg","family":"Chenail","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2501-8138","authenticated-orcid":true,"given":"James E.","family":"Audia","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Sims III","sequence":"additional","affiliation":[{"name":"Flare Therapeutics , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"2026091508070472400_cit1","doi-asserted-by":"publisher","DOI":"10.7554\/elife.61487","article-title":"Zinc shapes the\nfolding landscape of p53 and establishes a pathway for reactivating\nstructurally diverse cancer mutants","volume":"9","author":"Blanden","year":"2020","journal-title":"eLife"},{"key":"2026091508070472400_cit2","doi-asserted-by":"publisher","first-page":"2396","DOI":"10.1021\/bi026635n","article-title":"Structure, Function, and Aggregation\nof the Zinc-Free\nForm of the p53 DNA Binding Domain","volume":"42","author":"Butler","year":"2003","journal-title":"Biochemistry-us"},{"key":"2026091508070472400_cit3","doi-asserted-by":"publisher","first-page":"15056","DOI":"10.1073\/pnas.0607286103","article-title":"Structural basis for understanding\noncogenic p53 mutations and designing rescue drugs","volume":"103","author":"Joerger","year":"2006","journal-title":"Proc. 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