@article{786ab207e4354efdb33137fe0a116916,
title = "Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases",
abstract = "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 {\textquoteleft}molecular brake{\textquoteright}, {\textquoteleft}DFG latch{\textquoteright}, {\textquoteleft}A-loop plug{\textquoteright}, and {\textquoteleft}αC tether{\textquoteright}. 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.",
author = "Huaibin Chen and Marsiglia, {William M.} and Cho, {Min Kyu} and Zhifeng Huang and Jingjing Deng and Blais, {Steven P.} and Weiming Gai and Shibani Bhattacharya and Neubert, {Thomas A.} and Traaseth, {Nathaniel J.} and Moosa Mohammadi",
note = "Funding Information: This work was supported by the NIDCR grant DE13686 (to MM), NINDS grant P30 NS050276 (to TAN), and NIAID grant R01AI108889 (to NJT). Beamlines X-4A and X-4C at the National Synchrotron Light Source, Brookhaven National Laboratory (RRID:SCR_011123), a DOE facility, are supported by New York Structural Biology Consortium. The NMR data collected at NYU were supported by an NIH S10 grant (OD016343) while those NMR data acquired at the New York Structural Biology Center were supported by grants from NYSTAR and NIH (S10OD016432). The authors thank Prof. Arthur Palmer and Dr. Ying Li for sharing the backbone 15N TROSY-CPMG relaxation dispersion pulse sequence code for Bruker spectrometers. National Institute of Dental and Craniofacial Research DE13686 Moosa Mohammadi National Institute of Neurolo- gical Disorders and Stroke P30 NS050276 Thomas A Neubert National Institute of Allergy and Infectious Diseases R01AI108889 Nathaniel J Traaseth The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} Chen et al.",
year = "2017",
month = feb,
day = "6",
doi = "10.7554/eLife.21137",
language = "English (US)",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}