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ENS Cachan - Institut d'Alembert

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Recherche - Valorisation

Allosteric inhibition of the guanine nucleotide exchange factor DOCK5 by a small molecule

Ferrandez, Y., Zhang, W., Peurois, F., Akendengué, L., Blangy, A., Zeghouf, M., & Cherfils, J. (2017). Scientific Reports, 7(1), 14409.

SAXS analysis of DOCK5

SAXS analysis of DOCK5

Small GTPases are molecular switches in cellular signaling. They are turned on by GEFs, which stimulate the exchange of GDP by GTP. Here we studied the activation of the small GTPase Rac1 by it GEF DOCK5, which control bone homeostasis and are associated to osteoporosis. We combined fluorescence kinetics, synchrotron SAXS and crystallography to characterize the activation of Rac1 by DOCK5 and its inhibition by a small molecule, C21, which blocks bone degradation in mice models of osteoporosis (our collaboration with Dr A. Blangy, Vives et al. Nature Comm 2015). We show that Rac1 and DOCK5 feature intramolecular dynamics, which is diverted  by C21 to remodel the Rac1/DOCK5 complex into an unproductive conformation. We propose that intramolecular dynamics is an Achille's heal for allosteric inhibition of small GTPases in diseases.