Abstract
Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II. The kinase domain of fibroblast growth factor receptor 3 (FGFR3) falls into this family of kinases. We describe here, for the first time, its inactivation process through target molecular dynamics. The transient cavity, at the crossroad between the DFGout and Cα helix out inactivation is herein explored. Molecular docking calculations of known ligands demonstrated that type II inhibitors are able to interact with this metastable transient conformation of FGFR3 kinase. Besides, supplemental computations were conducted and clearly show that type II inhibitors drive the kinase inactivation process through specific stabilization with the DFG triad. This induced-fit effect of type II ligands toward FGFR3 might be extrapolated to other kinase systems and provides meaningful structural information for future drug developments.
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Acknowledgments
The China Scholarship Council is gratefully acknowledged for granting a Ph.D. scholarship to Yan LI. This work was granted access to the CINES (Centre Informatique National de l’Enseignement Supérieur, France) under the allocation c2013077022 made by GENCI (Grand Equipement National de Calcul Intensif). Financial support from the French agency ANR (Agence Nationale de la Recherche), under the program Grant name “ATAK”, is gratefully acknowledged.
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Li, Y., Delamar, M., Busca, P. et al. Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3). J Comput Aided Mol Des 29, 619–641 (2015). https://doi.org/10.1007/s10822-015-9841-8
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DOI: https://doi.org/10.1007/s10822-015-9841-8