{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:51:24Z","timestamp":1791222684877,"version":"4.1.0"},"reference-count":32,"publisher":"American Chemical Society (ACS)","issue":"17","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100000027","name":"Institute of Cancer Research","doi-asserted-by":"publisher","award":["481194"],"award-info":[{"award-number":["481194"]}],"id":[{"id":"10.13039\/501100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>FOXM1 is a cell proliferation-driving transcription factor activated by phosphorylation-induced conformational changes. In its inactive state, an intramolecular \u03b2-hairpin within the transactivation domain (TAD) binds the N-terminal repressor domain (NRD), forming a composite \u03b2-sheet that locks the protein in an autoinhibited conformation. Despite the known importance of this regulatory switch, the molecular events that unlock FOXM1 remain poorly characterized. Here, we performed 5 \u03bcs all-atom molecular dynamics simulations of human FOXM1b NRD-TAD complexes in both unphosphorylated and tetra-phosphorylated states, modeling four experimentally validated regulatory phosphosites. Our results showed that phosphorylation induces local unfolding of the \u03b2-hairpin beginning at Ser715, located at the hairpin turn, and propagates to global disruption of the NRD interface through hydrogen bond loss, salt bridge rupture, and secondary structure collapse. In contrast, the unphosphorylated complex maintains stable hairpin geometry and interdomain contacts. Additional replicate tetra-phosphorylated simulations and a monophosphorylated Ser715 simulation reproduced the \u03b2-hairpin unfolding event, supporting both reproducibility and the sufficiency of Ser715 phosphorylation in initiating this transition. Per-residue MM-PBSA energy decomposition further reveals that phosphorylation redistributes interdomain interaction energetics, with Ser715 emerging as the dominant locus of energetic perturbation despite the presence of multiple phosphosites. Together, these findings support a phosphorylation-triggered order-to-disorder transition that relieves FOXM1 autoinhibition and highlight Ser715 as a key structural and energetic switch. Our study provides a dynamic molecular framework for targeting FOXM1 activation via its regulatory fold.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01772","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:02:16Z","timestamp":1786698136000},"page":"11096-11105","source":"Crossref","is-referenced-by-count":1,"title":["Ser715 Phosphorylation\nInduces \u03b2-Hairpin\nUnfolding and Destabilization of FOXM1 Autoinhibition"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1347-5251","authenticated-orcid":true,"given":"Sara","family":"AlRawashdeh","sequence":"first","affiliation":[{"name":"University of Alberta , , ,","place":["Edmonton, Canada, AB T6G 2E1"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghd","family":"Obidat","sequence":"additional","affiliation":[{"name":"University of Alberta , , ,","place":["Edmonton, Canada, AB T6G 2E1"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aylin","family":"Del Moral-Morales","sequence":"additional","affiliation":[{"name":"Universidad Nacional Auto\u0301noma de Me\u0301xico , , Avenida Universidad 3000 , ,","place":["Mexico City, Mexico, C.P. 04510"]},{"name":"Universidad Auto\u0301noma Metropolitana-Cuajimalpa (UAM-C) , , ,","place":["Mexico City, Mexico, C.P. 05348"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4940-1107","authenticated-orcid":true,"given":"Jose\u0301 L.","family":"Medina-Franco","sequence":"additional","affiliation":[{"name":"Universidad Nacional Auto\u0301noma de Me\u0301xico , , Avenida Universidad 3000 , ,","place":["Mexico City, Mexico, C.P. 04510"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4535-1835","authenticated-orcid":true,"given":"Carlos A.","family":"Vela\u0301zquez-Marti\u0301nez","sequence":"additional","affiliation":[{"name":"University of Alberta , , ,","place":["Edmonton, Canada, AB T6G 2E1"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"2026091409082277300_cit1","doi-asserted-by":"publisher","DOI":"10.7554\/elife.46131","article-title":"An order-to-disorder structural switch activates the FoxM1 transcription\nfactor","volume":"8","author":"Marceau","year":"2019","journal-title":"eLife"},{"key":"2026091409082277300_cit2","doi-asserted-by":"publisher","first-page":"13625","DOI":"10.1093\/nar\/gkae988","article-title":"The conformation\nof FOXM1 homodimers in vivo is crucial for regulating transcriptional\nactivities","volume":"52","author":"Hsu","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"2026091409082277300_cit3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.semcancer.2023.03.007","article-title":"FOXM1:\nA small fox that makes more tracks for cancer progression and metastasis","volume":"92","author":"Khan","year":"2023","journal-title":"Semin. Cancer Biol."},{"key":"2026091409082277300_cit4","doi-asserted-by":"publisher","first-page":"218160","DOI":"10.1016\/j.canlet.2025.218160","article-title":"Targeting FOXM1 reshapes\nantitumor immunity to attenuate small cell\nlung cancer progression","volume":"638","author":"Khan","year":"2026","journal-title":"Cancer Lett."},{"key":"2026091409082277300_cit5","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.7150\/ijbs.105289","article-title":"FOXM1-Driven CKS1B Upregulation Promotes Pancreatic\nCancer Progression\nand Therapeutic Resistance","volume":"21","author":"Zhang","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"2026091409082277300_cit6","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1074\/jbc.M115.678227","article-title":"A Novel Function\nof Molecular Chaperone HSP70: Suppression of Oncogenic FOXM1 after\nProteotoxic Stress","volume":"291","author":"Halasi","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2026091409082277300_cit7","doi-asserted-by":"publisher","first-page":"4378","DOI":"10.7150\/jca.111013","article-title":"FoxM1 promotes\nTFAM expression and regulates Mitochondrial Dynamics in Glioblastoma\ncells","volume":"16","author":"Moazzam","year":"2025","journal-title":"J. Cancer"},{"key":"2026091409082277300_cit8","doi-asserted-by":"publisher","first-page":"2931","DOI":"10.1038\/s41467-025-57503-4","article-title":"FOXM1 expression reverts aging chromatin profiles through repression\nof the senescence-associated pioneer factor AP-1","volume":"16","author":"Ferreira","year":"2025","journal-title":"Nat. Commun."},{"key":"2026091409082277300_cit9","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1007\/s10238-023-01037-w","article-title":"The role of FoxM1 in\nimmune cells","volume":"23","author":"Zheng","year":"2023","journal-title":"Clin. Exp. 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(Weinh)."},{"key":"2026091409082277300_cit13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.semcancer.2022.07.009","article-title":"Dysregulated FOXM1 signaling\nin the regulation of cancer stem cells","volume":"86","author":"Sher","year":"2022","journal-title":"Semin.\nCancer Biol."},{"key":"2026091409082277300_cit14","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.bcp.2012.10.013","article-title":"Targeting FOXM1\nin cancer","volume":"85","author":"Halasi","year":"2013","journal-title":"Biochem.\nPharmacol."},{"key":"2026091409082277300_cit15","doi-asserted-by":"publisher","first-page":"1316","DOI":"10.1016\/j.bbagrm.2014.09.016","article-title":"FOXM1: an emerging master regulator\nof DNA damage response\nand genotoxic agent resistance","volume":"1839","author":"Zona","year":"2014","journal-title":"Biochim. Biophys.\nActa Gen. Subj."},{"key":"2026091409082277300_cit16","doi-asserted-by":"publisher","first-page":"857","DOI":"10.3390\/biom13050857","article-title":"FOXM1: Functional Roles\nof FOXM1 in Non-Malignant Diseases","volume":"13","author":"Zhang","year":"2023","journal-title":"Biomolecules"},{"key":"2026091409082277300_cit17","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1186\/s13046-022-02483-2","article-title":"Peptide-based\nPROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and\nPD-L1 expression","volume":"41","author":"Wang","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"2026091409082277300_cit18","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.1016\/j.molcel.2024.09.024","article-title":"Redirecting the pioneering function of FOXA1 with covalent\nsmall\nmolecules","volume":"84","author":"Won","year":"2024","journal-title":"Mol. 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Cancer Res."},{"key":"2026091409082277300_cit22","unstructured":"Chemical Computing Group.\n          \n          Molecular Operating Environment\n(MOE); 910-1010 Sherbooke St. West, Montreal,\nQC, Canada, H3A 2R7, Preprint at, 2015."},{"key":"2026091409082277300_cit23","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular\nsimulation programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"2026091409082277300_cit24","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1002\/wcms.1121","article-title":"An overview of the Amber biomolecular\nsimulation package","volume":"3","author":"Salomon-Ferrer","year":"2013","journal-title":"Wiley Interdiscip. Rev.\nComput. Mol. 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Spec.\nTop."},{"key":"2026091409082277300_cit30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual\nmolecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"2026091409082277300_cit31","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating structures and free energies of\ncomplex molecules: combining\nmolecular mechanics and continuum models","volume":"33","author":"Kollman","year":"2000","journal-title":"Acc.\nChem. Res."},{"key":"2026091409082277300_cit32","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.1021\/acs.jcim.0c00540","article-title":"How Do Small Molecule\nAggregates Inhibit Enzyme Activity? A Molecular Dynamics Study","volume":"60","author":"Ghattas","year":"2020","journal-title":"J. Chem. Inf. Model."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c01772","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/11096\/66542211\/acs.jcim.6c01772.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/11096\/66542211\/acs.jcim.6c01772.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:29:18Z","timestamp":1789392558000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/17\/11096\/5255222\/Ser715-Phosphorylation-Induces-Hairpin-Unfolding"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":32,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,8,14]]},"published-print":{"date-parts":[[2026,9,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c01772","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}