{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:08:08Z","timestamp":1790096888500,"version":"4.0.1"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"39","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA201380"],"award-info":[{"award-number":["R01CA201380"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:p>\n                    <jats:italic toggle=\"yes\">CREBBP<\/jats:italic>\n                    is among the most frequently mutated genes in human cancer and encodes a lysine acetyltransferase (KAT) protein that acetylates histones and nonhistone proteins to drive transcriptional activation. Mutations of\n                    <jats:italic toggle=\"yes\">CREBBP<\/jats:italic>\n                    most frequently result in missense changes affecting the active site within the KAT domain. However, there has not yet been comprehensive biochemical, structural, and functional studies to determine the impact of recurrent KAT-domain variants. Here we show that the most frequently mutated residue of\n                    <jats:italic toggle=\"yes\">CREBBP<\/jats:italic>\n                    , arginine 1446, alters the stability of acetyl-CoA binding within the cofactor-binding pocket but retains detectable acetyltransferase activity for a variety of substrates including histones. In contrast, other recurrently mutated residues affect the catalytic center within the KAT domain and result in a catalytically dead protein with a profound loss of histone acetylation and enhancer activity. These results highlight functionally divergent classes of\n                    <jats:italic toggle=\"yes\">CREBBP<\/jats:italic>\n                    mutations depending on the position of the mutated residue within KAT domain.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2605702123","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:12:31Z","timestamp":1790093551000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Structural and functional divergence of cancer hotspot mutations in CREBBP"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6815-7173","authenticated-orcid":false,"given":"Wenchao","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04twxam07","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer 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France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9292-5283","authenticated-orcid":false,"given":"Leslie","family":"Regad","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02z0jq636","id-type":"ROR","asserted-by":"publisher"}],"name":"Universit\u00e9 Paris Cit\u00e9, CNRS, Unit\u00e9 de Biologie Fonctionnelle et Adaptative","place":["Paris, France"]},{"name":"INSERM U1133, Computational Modeling of Protein-Ligand Interactions","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5785-0685","authenticated-orcid":false,"given":"Romain","family":"Duval","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9 and Universit\u00e9 des Antilles, INSERM, UMRS 1134","place":["Paris, France"]},{"id":[{"id":"https:\/\/ror.org\/037hby126","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre National de R\u00e9f\u00e9rence pour les Groupes Sanguins, \u00c9tablissement Fran\u00e7ais du Sang Ile-de-France","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Dairou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gaw1s20","id-type":"ROR","asserted-by":"publisher"}],"name":"Universit\u00e9 Paris Cit\u00e9, CNRS UMR 8601, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1196-1635","authenticated-orcid":false,"given":"Ahmed","family":"Haouz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f82e368","id-type":"ROR","asserted-by":"publisher"}],"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3528, Plate-forme de Cristallographie-C2RT","place":["Paris, 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