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

Scientific Reports
Yann FerrandezJacqueline Cherfils

Abstract

Rac small GTPases and their GEFs of the DOCK family are pivotal checkpoints in development, autoimmunity and bone homeostasis, and their abnormal regulation is associated to diverse pathologies. Small molecules that inhibit their activities are therefore needed to investigate their functions. Here, we characterized the mechanism of inhibition of human DOCK5 by C21, a small molecule that inhibits mouse Dock5 in cells and blocks bone degradation in mice models of osteoporosis. We showed that the catalytic DHR2 domain of DOCK5 has a high basal GEF activity in the absence of membranes which is not regulated by a simple feedback loop. C21 blocks this activity in a non-competitive manner and is specific for DOCK5. In contrast, another Dock inhibitor, CPYPP, inhibits both DOCK5 and an unrelated GEF, Trio. To gain insight into structural features of the inhibitory mechanism of C21, we used SAXS analysis of DOCK5DHR2 and crystallographic analysis of unbound Rac1-GDP. Together, these data suggest that C21 takes advantage of intramolecular dynamics of DOCK5 and Rac1 to remodel the complex into an unproductive conformation. Based on this allosteric mechanism, we propose that diversion of intramolecular dynamics is a potent mechanism for th...Continue Reading

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Citations

Apr 30, 2019·Small GTPases·Ian Aj Lorimer
May 16, 2019·The Journal of Biological Chemistry·Ryan C Killoran, Matthew J Smith
Aug 29, 2019·Biology of the Cell·Sarah GuimbalVirginie Vives
Mar 15, 2019·Angewandte Chemie·Janine L GrayPaul E Brennan
Jul 9, 2020·The Journal of Biological Chemistry·Megan E ArringtonSharon L Campbell
Apr 24, 2020·Frontiers in Cell and Developmental Biology·Maria Del Mar MaldonadoSuranganie Dharmawardhane
Mar 9, 2021·The Journal of Biological Chemistry·Andrew P ThompsonPaul E Brennan
Apr 14, 2021·The Journal of Physical Chemistry. B·Simge SenyuzAttila Gursoy
Jun 27, 2021·British Journal of Cancer·Oscar MaiquesGilbert O Fruhwirth
Sep 11, 2021·Current Opinion in Structural Biology·Mutsuko Kukimoto-NiinoMikako Shirouzu

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Methods Mentioned

BETA
GTPases
nucleotide exchange
GTPase
Fluorescence
X-ray
size exclusion chromatography
size
gel filtration

Software Mentioned

SUPCOMB
CRYSOL
Dadimodo
ATSAS
PRIMUS
GNOM
BUSTER
DAMMIF
Tasser
Coot

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