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Role of the N‐Terminal Transmembrane Helix Contacts in the Activation of FGFR3
Author(s) -
Matsuoka Daisuke,
Kamiya Motoshi,
Sato Takeshi,
Sugita Yuji
Publication year - 2020
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.26122
Subject(s) - dimer , helix (gastropod) , transmembrane domain , chemistry , receptor tyrosine kinase , transmembrane protein , biophysics , extracellular , nuclear magnetic resonance spectroscopy , crystallography , protein kinase domain , kinase , receptor , mutant , stereochemistry , biochemistry , biology , ecology , organic chemistry , snail , gene
Fibroblast growth factor receptor 3 (FGFR3) is a member of receptor tyrosine kinases, which is involved in skeletal cell growth, differentiation, and migration. FGFR3 transduces biochemical signals from the extracellular ligand‐binding domain to the intracellular kinase domain through the conformational changes of the transmembrane (TM) helix dimer. Here, we apply generalized replica exchange with solute tempering method to wild type (WT) and G380R mutant (G380R) of FGFR3. The dimer interface in G380R is different from WT and the simulation results are in good agreement with the solid‐state nuclear magnetic resonance (NMR) spectroscopy. TM helices in G380R are extended more than WT, and thereby, G375 in G380R contacts near the N‐termini of the TM helix dimer. Considering that both G380R and G375C show the constitutive activation, the formation of the N‐terminal contacts of the TM helices can be generally important for the activation mechanism. © 2019 Wiley Periodicals, Inc.