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These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2\u2013FGF2 affinity. Moreover, based on these structures and sequence alignment of the FGF family, we propose that the Pro-253 \u2192 Arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the Ser-252 \u2192 Trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of AS mutations on FGF binding. Alterations in FGFR2 ligand affinity and specificity may allow inappropriate autocrine or paracrine activation of FGFR2. Furthermore, the distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among AS patients.<\/jats:p>","DOI":"10.1073\/pnas.121183798","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:37:36Z","timestamp":1027679856000},"page":"7182-7187","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":167,"title":["Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome"],"prefix":"10.1073","volume":"98","author":[{"given":"Omar A.","family":"Ibrahimi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, New York University School of Medicine, New York, NY 10016; and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna V.","family":"Eliseenkova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, New York University School of Medicine, New York, NY 10016; and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander N.","family":"Plotnikov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, New York University School of Medicine, New York, NY 10016; and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, New York University School of Medicine, New York, NY 10016; and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Ornitz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, New York University School of Medicine, New York, NY 10016; and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moosa","family":"Mohammadi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, New York University School of Medicine, New York, NY 10016; and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,6,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1247\/csf.25.85","volume":"25","author":"McIntosh I","year":"2000","unstructured":"I McIntosh, G A Bellus, E W Jabs Cell Struct Funct 25, 85\u201396 (2000).","journal-title":"Cell Struct Funct"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S1010-5182(97)80048-0","volume":"25","author":"Gorlin R J","year":"1997","unstructured":"R J Gorlin J Craniomaxillofac Surg 25, 69\u201379 (1997).","journal-title":"J Craniomaxillofac Surg"},{"key":"e_1_3_4_3_2","first-page":"139","volume":"68","author":"Hehr U","year":"1999","unstructured":"U Hehr, M Muenke Mol Genet 68, 139\u2013151 (1999).","journal-title":"Mol Genet"},{"key":"e_1_3_4_4_2","first-page":"1310","volume":"23","author":"Apert M E","year":"1906","unstructured":"M E Apert Bull Soc Med H\u00f4p Paris 23, 1310\u20131313 (1906).","journal-title":"Bull Soc Med H\u00f4p Paris"},{"key":"e_1_3_4_5_2","first-page":"923","volume":"58","author":"Slaney S F","year":"1996","unstructured":"S F Slaney, M Oldridge, J A Hurst, G M Moriss-Kay, C M Hall, M D Poole, A O Wilkie Am J Hum Genet 58, 923\u2013932 (1996).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3171\/jns.1999.90.3.0443","volume":"90","author":"Lajeunie E","year":"1999","unstructured":"E Lajeunie, R Cameron, V El-Ghouzzi, N de Parseval, P Journeau, M Gonzales, A L Delezoide, J Bonaventure, M Le Merrer, D Renier J Neurosurg 90, 443\u2013447 (1999).","journal-title":"J Neurosurg"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/ng0295-165","volume":"9","author":"Wilkie A O M","year":"1995","unstructured":"A O M Wilkie, S F Slaney, M Oldridge, M D Poole, G J Ashworth, A D Hockley, R D Hayward, D J David, L J Pulleyn, P Rutland, et al. 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