title: Nuclear magnetic resonance analysis of the conformational state of cancer mutant of fibroblast growth factor receptor 1 tyrosine kinase domain.
abstract: Tyrosine kinases are key enzymes that play critical roles in growth signaling, the abnormal activation of which is associated with various human cancers. Activation of tyrosine kinases is mediated by tyrosine phosphorylation in the activation-loop, which transforms the catalytic domain to the active state conformation. Cancer mutations are supposed to transform the conformation of the catalytic domain into the active-form independent of the phosphorylation state of the activation-loop. Here, we report structural and biophysical analyses of cancer mutations of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1). Based on the nuclear magnetic resonance analyses, phosphorylation of the activation-loop exhibited cooperative structural transition in the activation-loop, C-helix and P-loop regions, whereas cancer mutations induced structural transformation at either one or two of these regions.
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Yoshihiro
authors: Y
authors: Kobashigawa
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 060-0810, Japan.
authors: Shinjiro
authors: S
authors: Amano
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Kaito
authors: K
authors: Yoza
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Rika
authors: R
authors: Himeno
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Shun
authors: S
authors: Amemiya
authors: Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
authors: Hiroshi
authors: H
authors: Morioka
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 060-0810, Japan.
authors: Mariko
authors: M
authors: Yokogawa
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 060-0810, Japan.
authors: Hiroyuki
authors: H
authors: Kumeta
authors: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors: Joseph
authors: J
authors: Schlessinger
authors: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 060-0810, Japan.
authors: Fuyuhiko
authors: F
authors: Inagaki
mesh_terms: D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D011487:Protein Conformation; D000072417:Protein Domains; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry* / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism
chemical_list: C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1