4j96 Citations

Cracking the molecular origin of intrinsic tyrosine kinase activity through analysis of pathogenic gain-of-function mutations.

Cell Rep 4 376-84 (2013)
Related entries: 4j95, 4j97, 4j98, 4j99

Cited: 27 times
EuropePMC logo PMID: 23871672

Abstract

The basal (ligand-independent) kinase activity of receptor tyrosine kinases (RTKs) promotes trans-phosphorylation on activation loop tyrosines upon ligand-induced receptor dimerization, thus upregulating intrinsic kinase activity and triggering intracellular signaling. To understand the molecular determinants of intrinsic kinase activity, we used X-ray crystallography and NMR spectroscopy to analyze pathogenic FGF receptor mutants with gradations in gain-of-function activity. These structural analyses revealed a "two-state" dynamic equilibrium model whereby the kinase toggles between an "inhibited," structurally rigid ground state and a more dynamic and heterogeneous active state. The pathogenic mutations have different abilities to shift this equilibrium toward the active state. The increase in the fractional population of FGF receptors in the active state correlates with the degree of gain-of-function activity and clinical severity. Our data demonstrate that the fractional population of RTKs in the active state determines intrinsic kinase activity and underscore how a slight increase in the active population of kinases can have grave consequences for human health.

Articles - 4j96 mentioned but not cited (5)

  1. Cracking the molecular origin of intrinsic tyrosine kinase activity through analysis of pathogenic gain-of-function mutations. Chen H, Huang Z, Dutta K, Blais S, Neubert TA, Li X, Cowburn D, Traaseth NJ, Mohammadi M. Cell Rep 4 376-384 (2013)
  2. Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases. Chen H, Marsiglia WM, Cho MK, Huang Z, Deng J, Blais SP, Gai W, Bhattacharya S, Neubert TA, Traaseth NJ, Mohammadi M. Elife 6 e21137 (2017)
  3. Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer. Nakamura IT, Kohsaka S, Ikegami M, Ikeuchi H, Ueno T, Li K, Beyett TS, Koyama T, Shimizu T, Yamamoto N, Takahashi F, Takahashi K, Eck MJ, Mano H. NPJ Precis Oncol 5 66 (2021)
  4. Effects of FGFR2 kinase activation loop dynamics on catalytic activity. Karp JM, Sparks S, Cowburn D. PLoS Comput Biol 13 e1005360 (2017)
  5. Synthesis, characterization, DFT calculations and biological activity of new Schiff base complexes. Alkhatib FM, Alsulami HM. Heliyon 9 e18988 (2023)


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