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A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.

Chen H, Ma J, Li W, Eliseenkova AV, Xu C, Neubert TA, Miller WT, Mohammadi M
Mol Cell 27 717-30 (2007)
Related entries: 2psq, 2pvf, 2pvy, 2pwl, 2pz5, 2pzp, 2pzr, 2q0b

Cited: 153 times
EuropePMC logo PMID: 17803937

Abstract

Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory "molecular brake" mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.

Articles - 2py3 mentioned but not cited (4)

  1. The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors. Byron SA, Chen H, Wortmann A, Loch D, Gartside MG, Dehkhoda F, Blais SP, Neubert TA, Mohammadi M, Pollock PM. Neoplasia 15 975-988 (2013)
  2. The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study. Bunney TD, Wan S, Thiyagarajan N, Sutto L, Williams SV, Ashford P, Koss H, Knowles MA, Gervasio FL, Coveney PV, Katan M. EBioMedicine 2 194-204 (2015)
  3. 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)
  4. Effects of FGFR2 kinase activation loop dynamics on catalytic activity. Karp JM, Sparks S, Cowburn D. PLoS Comput Biol 13 e1005360 (2017)


Reviews citing this publication (44)

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Articles citing this publication (105)



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