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Cited by 37Protein Kinase Regulation and GTPase SignalingReceptor Mechanisms and SignalingBone Metabolism and Diseases

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

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Ferrandez, Yann, Zhang, Wenhua, Peurois, François, Akendengué, Lurlène, Blangy, Anne, Zeghouf, Mahel, Cherfils, Jacqueline·2017·Scientific Reports
DOI 10.1038/s41598-017-13619-2PMC PMC5663973
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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 DOCK5 DHR2 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 the inhibition of multidomain regulators of small GTPases.

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  • DOCK5 preferentially activates RAC1 over other RHO or RAC GTPases.

    “DOCK5, one of the least studied family members, preferentially activates RAC1 over other RHO or RAC GTPases (91).”

    From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [91]

    The Results section (‘Specificity and regulation of the DHR2 domain of human DOCK5’) reports that DOCK5DHR2 activates Rac1 and Rac2 with nearly identical efficiencies: 3 × 10⁴ and 3.2 × 10⁴ M⁻¹s⁻¹, respectively. It is inactive toward the tested RhoA, Cdc42, and RhoG, but the results do not show a preference for Rac1 over other Rac GTPases. (LLM, conf=0.90)

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Authors
Ferrandez, Y., Zhang, W., Peurois, F., Akendengué, L., Blangy, A., Zeghouf, M., & Cherfils, J.
Affiliations
  • École Normale Supérieure Paris-Saclay (FR)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Cherfils, Jacqueline
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-10-31
Volume
7
Issue
1
Pages
14409-14409
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-13619-2
PMC
PMC5663973
OpenAlex
W2765281369
Cited by
37
References
2
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 1 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 1
FWCI
1.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-14-CE09-0028, ANR-10-LABX-0033)
  • Centre National de la Recherche Scientifique
  • Institut National Du Cancer
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Keywords
DOCK5, allosteric inhibition, guanine nucleotide exchange factor, C21, trios, non-competitive inhibition, intramolecular dynamics, osteoporosis, bone degradation, small molecule inhibitors
MeSH terms
Allosteric Regulation, Chromatography, Escherichia coli, Guanosine Diphosphate, Humans, Kinetics, Liposomes, Models, Molecular, Pyrazoles, Sulfonamides, X-Ray Diffraction, Protein Serine-Threonine Kinases, Guanine Nucleotide Exchange Factors, rac1 GTP-Binding Protein, Bone Density Conservation Agents, Scattering, Small Angle

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