{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:12:23Z","timestamp":1788477143820,"version":"build-2803163510"},"reference-count":51,"publisher":"American Chemical Society (ACS)","issue":"6","license":[{"start":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T00:00:00Z","timestamp":1561334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/na","name":"Research Enhancement Fund, University of Texas at Dallas","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":[[2019,6,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Forkhead transcription factor C2 (FOXC2) is a transcription factor regulating vascular and lymphatic development, and its mutations are linked to lymphedema-distichiasis syndrome. FOXC2 is also a crucial regulator of the epithelial\u2013mesenchymal transition processes essential for tumor metastasis. Here, we report the crystal structure of the FOXC2\u2013DNA-binding domain in complex with its cognate DNA. The crystal structure provides the basis of DNA sequence recognition by FOXC2 for the T\/CAAAC motif. Helix 3 makes the majority of the DNA\u2013protein interactions and confers the DNA sequence specificity. The computational energy calculation results also validate the structural observations. The FOXC2 and DNA complex structure provides a detailed picture of protein and DNA interactions, which allows us to predict its DNA recognition specificity and impaired functions in mutants identified in human patients.<\/jats:p>","DOI":"10.1021\/acsomega.9b00756","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T12:59:33Z","timestamp":1561467573000},"page":"10906-10914","source":"Crossref","is-referenced-by-count":9,"title":["Crystal Structure of FOXC2 in Complex with DNA Target"],"prefix":"10.1021","volume":"4","author":[{"given":"Shichang","family":"Li","sequence":"first","affiliation":[{"name":"The University of Texas at Dallas , , 800 W. Campbell Road , , ,","place":["Richardson, Texas, United States, 75080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lagnajeet","family":"Pradhan","sequence":"additional","affiliation":[{"name":"The University of Texas at Dallas , , 800 W. Campbell Road , , ,","place":["Richardson, Texas, United States, 75080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayan","family":"Ashur","sequence":"additional","affiliation":[{"name":"The University of Texas at Dallas , , 800 W. Campbell Road , , ,","place":["Richardson, Texas, United States, 75080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshu","family":"Joshi","sequence":"additional","affiliation":[{"name":"The University of Texas at Dallas , , 800 W. Campbell Road , , ,","place":["Richardson, Texas, United States, 75080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0235-9311","authenticated-orcid":true,"given":"Hyun-Joo","family":"Nam","sequence":"additional","affiliation":[{"name":"The University of Texas at Dallas , , 800 W. Campbell Road , , ,","place":["Richardson, Texas, United States, 75080"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,6,24]]},"reference":[{"key":"2026090318135952900_cit1","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial-mesenchymal transition generates cells\nwith properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"2026090318135952900_cit2","doi-asserted-by":"publisher","first-page":"10069","DOI":"10.1073\/pnas.0703900104","article-title":"Mesenchyme Forkhead\n1 (FOXC2) plays\na key role in metastasis and is associated with aggressive basal-like\nbreast cancers","volume":"104","author":"Mani","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090318135952900_cit3","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1158\/0008-5472.CAN-12-2962","article-title":"FOXC2 expression\nlinks epithelial-mesenchymal transition and stem cell properties in\nbreast cancer","volume":"73","author":"Hollier","year":"2013","journal-title":"Cancer Res."},{"key":"2026090318135952900_cit4","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/nrc3447","article-title":"Regulatory networks defining EMT\nduring cancer initiation and progression","volume":"13","author":"De Craene","year":"2013","journal-title":"Nat.\nRev. Cancer"},{"key":"2026090318135952900_cit5","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/204593","article-title":"The Role of\nFoxC2 Transcription Factor in Tumor Angiogenesis","volume":"2012","author":"Kume","year":"2012","journal-title":"J. Oncol."},{"key":"2026090318135952900_cit6","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1245\/s10434-010-1274-y","article-title":"FOXC2 is a\nNovel Prognostic Factor in Human Esophageal Squamous Cell Carcinoma","volume":"18","author":"Nishida","year":"2011","journal-title":"Ann. Surg. Oncol."},{"key":"2026090318135952900_cit7","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.bbrc.2010.01.015","article-title":"The Foxc2\ntranscription factor regulates\ntumor angiogenesis","volume":"392","author":"Sano","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2026090318135952900_cit8","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/204593","article-title":"The Role of\nFoxC2 Transcription Factor in Tumor Angiogenesis","volume":"2012","author":"Kume","year":"2012","journal-title":"J. Oncol."},{"key":"2026090318135952900_cit9","doi-asserted-by":"publisher","first-page":"5963","DOI":"10.1038\/onc.2015.498","article-title":"Inhibition of FOXC2 restores epithelial\nphenotype and drug sensitivity in prostate cancer cells with stem-cell\nproperties","volume":"35","author":"Paranjape","year":"2016","journal-title":"Oncogene"},{"key":"2026090318135952900_cit10","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1002\/cbic.201800022","article-title":"A Forkhead Box Protein\nC2 Inhibitor: Targeting Epithelial-Mesenchymal Transition and Cancer\nMetastasis","volume":"19","author":"Castaneda","year":"2018","journal-title":"ChemBioChem"},{"key":"2026090318135952900_cit11","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1038\/nrc2223","article-title":"The emerging roles of forkhead box (Fox) proteins in\ncancer","volume":"7","author":"Myatt","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"2026090318135952900_cit12","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1186\/1479-7364-4-5-345","article-title":"Update of human and\nmouse forkhead box (FOX) gene families","volume":"4","author":"Jackson","year":"2010","journal-title":"Hum.\nGenomics"},{"key":"2026090318135952900_cit13","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1101\/gad.14.2.142","article-title":"Unified\nnomenclature for the winged\nhelix\/forkhead transcription factors","volume":"14","author":"Kaestner","year":"2000","journal-title":"Genes\nDev."},{"key":"2026090318135952900_cit14","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.tig.2011.03.003","article-title":"Forkhead\ntranscription factors: key\nplayers in health and disease","volume":"27","author":"Benayoun","year":"2011","journal-title":"Trends Genet."},{"key":"2026090318135952900_cit15","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/S0168-9525(03)00111-2","article-title":"Fox\u2019s\nin development and disease","volume":"19","author":"Lehmann","year":"2003","journal-title":"Trends Genet."},{"key":"2026090318135952900_cit16","doi-asserted-by":"publisher","first-page":"2802","DOI":"10.1002\/ajmg.a.36736","article-title":"A five generation\nfamily with a novel mutation in FOXC2 and lymphedema worsening to\nhydrops in the youngest generation","volume":"164","author":"Sargent","year":"2014","journal-title":"Am. J. Med.\nGenet., Part A"},{"key":"2026090318135952900_cit17","first-page":"98","article-title":"Novel FOXC2 missense mutation identified\nin patient\nwith lymphedema-distichiasis syndrome and review","volume":"41","author":"Dellinger","year":"2008","journal-title":"Lymphology"},{"key":"2026090318135952900_cit18","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1086\/316915","article-title":"Mutations in FOXC2\n(MFH-1), a forkhead family transcription factor, are responsible for\nthe hereditary lymphedema-distichiasis syndrome","volume":"67","author":"Fang","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"2026090318135952900_cit19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1006\/dbio.2002.0780","article-title":"Forkhead transcription\nfactors: key players in development\nand metabolism","volume":"250","author":"Carlsson","year":"2002","journal-title":"Dev. Biol."},{"key":"2026090318135952900_cit20","doi-asserted-by":"publisher","first-page":"4702","DOI":"10.1038\/onc.2014.395","article-title":"Casein kinase 2 prevents mesenchymal transformation\nby maintaining Foxc2 in the cytoplasm","volume":"34","author":"Golden","year":"2015","journal-title":"Oncogene"},{"key":"2026090318135952900_cit21","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1002\/pro.626","article-title":"Solution structure and backbone dynamics\nof the DNA-binding\ndomain of FOXP1: insight into its domain swapping and DNA binding","volume":"20","author":"Chu","year":"2011","journal-title":"Protein Sci."},{"key":"2026090318135952900_cit22","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1006\/jmbi.1999.2819","article-title":"Dynamic DNA contacts\nobserved in the NMR structure of winged helix protein-DNA complex","volume":"289","author":"Jin","year":"1999","journal-title":"J. Mol. Biol."},{"key":"2026090318135952900_cit23","doi-asserted-by":"publisher","first-page":"11261","DOI":"10.1073\/pnas.2031918100","article-title":"NMR structure\nof the forkhead-associated domain from the Arabidopsis receptor kinase-associated\nprotein phosphatase","volume":"100","author":"Lee","year":"2003","journal-title":"Proc. Natl. Acad. Sci.\nU.S.A."},{"key":"2026090318135952900_cit24","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1002\/prot.10227","article-title":"Solution structure\nof the DNA-binding domain of interleukin enhancer binding factor 1\n(FOXK1a)","volume":"49","author":"Liu","year":"2002","journal-title":"Proteins"},{"key":"2026090318135952900_cit25","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1021\/bi011908k","article-title":"Structure comparison of two conserved\nHNF-3\/fkh proteins HFH-1 and genesis indicates the existence of folding\ndifferences in their complexes with a DNA binding sequence","volume":"41","author":"Sheng","year":"2002","journal-title":"Biochemistry"},{"key":"2026090318135952900_cit26","doi-asserted-by":"publisher","first-page":"5861","DOI":"10.1021\/bi001663w","article-title":"Solution structure\nof the DNA binding domain of the human forkhead transcription factor\nAFX (FOXO4)","volume":"40","author":"Weigelt","year":"2001","journal-title":"Biochemistry"},{"key":"2026090318135952900_cit27","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1006\/jmbi.1999.3476","article-title":"Solution structure and dynamics of the DNA-binding\ndomain of the adipocyte-transcription factor FREAC-11","volume":"296","author":"van Dongen","year":"2000","journal-title":"J. Mol. Biol."},{"key":"2026090318135952900_cit28","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.immuni.2011.02.017","article-title":"Structure\nof a domain-swapped FOXP3 dimer on DNA and its function\nin regulatory T cells","volume":"34","author":"Bandukwala","year":"2011","journal-title":"Immunity"},{"key":"2026090318135952900_cit29","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1107\/S0907444910042228","article-title":"Structure\nof the human FOXO4-DBD-DNA complex at 1.9 A resolution reveals new\ndetails of FOXO binding to the DNA","volume":"66","author":"Boura","year":"2010","journal-title":"Acta Crystallogr.,\nSect. D: Struct. Biol."},{"key":"2026090318135952900_cit30","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1093\/nar\/gkq194","article-title":"Structure of the FoxM1\nDNA-recognition domain bound to a promoter sequence","volume":"38","author":"Littler","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2026090318135952900_cit31","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.str.2005.10.005","article-title":"Structure of the forkhead domain\nof FOXP2 bound to DNA","volume":"14","author":"Stroud","year":"2006","journal-title":"Structure"},{"key":"2026090318135952900_cit32","doi-asserted-by":"publisher","first-page":"6984","DOI":"10.1093\/nar\/gkm703","article-title":"Crystal structure of the human FOXO3a-DBD\/DNA\ncomplex\nsuggests the effects of post-translational modification","volume":"35","author":"Tsai","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2026090318135952900_cit33","doi-asserted-by":"publisher","first-page":"3752","DOI":"10.1093\/nar\/gkz077","article-title":"Structural\nbasis for DNA recognition by FOXC2","volume":"47","author":"Chen","year":"2019","journal-title":"Nucleic\nAcids Res."},{"key":"2026090318135952900_cit34","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1107\/S1399004715000139","article-title":"NuProPlot: nucleic\nacid and protein interaction analysis\nand plotting program","volume":"71","author":"Pradhan","year":"2015","journal-title":"Acta Crystallogr., Sect.\nD: Struct. Biol."},{"key":"2026090318135952900_cit35","doi-asserted-by":"publisher","first-page":"W382","DOI":"10.1093\/nar\/gki387","article-title":"The FoldX web server: an online force\nfield","volume":"33","author":"Schymkowitz","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2026090318135952900_cit36","doi-asserted-by":"publisher","DOI":"10.1038\/hgv.2015.32","article-title":"A novel FOXC2 mutation\nin spinal extradural arachnoid cyst","volume":"2","author":"Ogura","year":"2015","journal-title":"Hum. Genome\nVar."},{"key":"2026090318135952900_cit37","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1097\/GIM.0b013e3181e5c7ea","article-title":"Spinal extradural\narachnoid cysts in lymphedema-distichiasis syndrome","volume":"12","author":"Sa\u0301nchez-Carpintero","year":"2010","journal-title":"Genet. Med."},{"key":"2026090318135952900_cit38","doi-asserted-by":"publisher","first-page":"E1002","DOI":"10.1002\/humu.21127","article-title":"Novel missense mutations\nin the FOXC2 gene alter transcriptional activity","volume":"30","author":"van Steensel","year":"2009","journal-title":"Hum. Mutat."},{"key":"2026090318135952900_cit39","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1093\/nar\/gkl1155","article-title":"Structure-based prediction\nof C2H2 zinc-finger binding specificity:\nsensitivity to docking geometry","volume":"35","author":"Siggers","year":"2007","journal-title":"Nucleic Acids\nRes."},{"key":"2026090318135952900_cit40","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1016\/j.cell.2008.10.049","article-title":"Combinatorial\nregulation of endothelial gene expression by ets and forkhead transcription\nfactors","volume":"135","author":"De Val","year":"2008","journal-title":"Cell"},{"key":"2026090318135952900_cit41","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1107\/S2053230X13024795","article-title":"Crystallization\nand preliminary X-ray analysis of a complex of the FOXO1 and Ets1\nDNA-binding domains and DNA","volume":"70","author":"Choy","year":"2014","journal-title":"Acta Crystallogr.,\nSect. F: Struct. Biol. Commun."},{"key":"2026090318135952900_cit42","doi-asserted-by":"publisher","first-page":"2714","DOI":"10.1002\/elps.1150181505","article-title":"SWISS-MODEL and\nthe Swiss-PdbViewer: an environment\nfor comparative protein modeling","volume":"18","author":"Guex","year":"1997","journal-title":"Electrophoresis"},{"key":"2026090318135952900_cit43","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.1021\/acs.biochem.6b00171","article-title":"Intermolecular Interactions\nof Cardiac\nTranscription Factors NKX2.5 and TBX5","volume":"55","author":"Pradhan","year":"2016","journal-title":"Biochemistry"},{"key":"2026090318135952900_cit44","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/0022-2836(68)90205-2","article-title":"Solvent\ncontent of protein crystals","volume":"33","author":"Matthews","year":"1968","journal-title":"J. Mol. Biol."},{"key":"2026090318135952900_cit45","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser\ncrystallographic software","volume":"40","author":"McCoy","year":"2007","journal-title":"J. Appl. Crystallogr."},{"key":"2026090318135952900_cit46","doi-asserted-by":"publisher","first-page":"6312","DOI":"10.1021\/bi300849c","article-title":"Crystal structure\nof the human NKX2.5 homeodomain in\ncomplex with DNA target","volume":"51","author":"Pradhan","year":"2012","journal-title":"Biochemistry"},{"key":"2026090318135952900_cit47","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jmb.2010.04.052","article-title":"Structural basis\nof TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound\nform","volume":"400","author":"Stirnimann","year":"2010","journal-title":"J. Mol. Biol."},{"key":"2026090318135952900_cit48","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive\nPython-based\nsystem for macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallogr., Sect. D: Struct. Biol."},{"key":"2026090318135952900_cit49","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: model-building tools for molecular\ngraphics","volume":"60","author":"Emsley","year":"2004","journal-title":"Acta Crystallogr., Sect. D: Struct.\nBiol."},{"key":"2026090318135952900_cit50","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","article-title":"MolProbity: all-atom structure validation for macromolecular\ncrystallography","volume":"66","author":"Chen","year":"2010","journal-title":"Acta Crystallogr., Sect. D:\nStruct. Biol."},{"key":"2026090318135952900_cit51","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image\nto ImageJ: 25 years of\nimage analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.9b00756","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/4\/6\/10906\/68314768\/acsomega.9b00756.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/4\/6\/10906\/68314768\/acsomega.9b00756.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T22:14:02Z","timestamp":1788473642000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/4\/6\/10906\/612549\/Crystal-Structure-of-FOXC2-in-Complex-with-DNA"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,24]]},"references-count":51,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6,24]]},"published-print":{"date-parts":[[2019,6,30]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.9b00756","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,24]]}}}