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Genes Cells. 2016 Apr;21(4):350-7. doi: 10.1111/gtc.12345. Epub 2016 Feb 10.

Nuclear magnetic resonance analysis of the conformational state of cancer mutant of fibroblast growth factor receptor 1 tyrosine kinase domain.

Author information

1
Department of Analytical and Biophysical Chemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
2
Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, Sapporo, 060-0810, Japan.
3
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.

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.

PMID:
26864631
DOI:
10.1111/gtc.12345
[Indexed for MEDLINE]
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