Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases

Huaibin Chen, William M. Marsiglia, Min Kyu Cho, Zhifeng Huang, Jingjing Deng, Steven P. Blais, Weiming Gai, Shibani Bhattacharya, Thomas A. Neubert, Nathaniel J. Traaseth, Moosa Mohammadi

Research output: Contribution to journalArticlepeer-review


Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the ‘molecular brake’, ‘DFG latch’, ‘A-loop plug’, and ‘αC tether’. The first three sites repress the kinase from adopting an active conformation, whereas the αC tether promotes the active conformation. The skewed design of this four-site allosteric network imposes tight autoinhibition and accounts for the incomplete mimicry of the activated conformation by pathogenic mutations targeting a single site. Based on the structural similarity shared among RTKs, we propose that this allosteric model for FGFR kinases is applicable to other RTKs.

Original languageEnglish (US)
Article numbere21137
StatePublished - Feb 6 2017

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


Dive into the research topics of 'Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases'. Together they form a unique fingerprint.

Cite this