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Cited by 403Genetic and Kidney Cyst DiseasesMicrotubule and mitosis dynamicsCystic Fibrosis Research Advances

Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein

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Firestone, Ari J., Weinger, Joshua S., Maldonado, Maria, Barlan, Kari, Langston, Lance D., O’Donnell, Michael, Gelfand, Vladimir I., Kapoor, Tarun M. +1 more·2012·Nature
DOI 10.1038/nature10936PMC PMC3321072
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Abstract

The conversion of chemical energy into mechanical force by AAA+ (ATPases associated with diverse cellular activities) ATPases is integral to cellular processes, including DNA replication, protein unfolding, cargo transport and membrane fusion. The AAA+ ATPase motor cytoplasmic dynein regulates ciliary trafficking, mitotic spindle formation and organelle transport, and dissecting its precise functions has been challenging because of its rapid timescale of action and the lack of cell-permeable, chemical modulators. Here we describe the discovery of ciliobrevins, the first specific small-molecule antagonists of cytoplasmic dynein. Ciliobrevins perturb protein trafficking within the primary cilium, leading to their malformation and Hedgehog signalling blockade. Ciliobrevins also prevent spindle pole focusing, kinetochore-microtubule attachment, melanosome aggregation and peroxisome motility in cultured cells. We further demonstrate the ability of ciliobrevins to block dynein-dependent microtubule gliding and ATPase activity in vitro. Ciliobrevins therefore will be useful reagents for studying cellular processes that require this microtubule motor and may guide the development of additional AAA+ ATPase superfamily inhibitors.

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  • Previous literature reported that a higher concentration of ciliobrevin D (100 μM) also inhibited kinesin-1 and kinesin-5 motor activity.

    “Concentration of ciliobrevin D, 50 μM, was based on previous literature that reported higher concentration, 100 μM, also inhibited kinesin-1 and kinesin-5 motor activity (18).”

    From Active transport by cytoplasmic dynein sustains dendritic MAP2 localization in developing neurons (2026) · cites this paper as [18]

    In the passage discussing Fig. 4d (page unavailable), the paper reports that neither ciliobrevin A nor D significantly affected kinesin-1-dependent microtubule gliding at 100 μM. The passage discussing Fig. 4e likewise says the compounds did not significantly inhibit kinesin-1 or kinesin-5 motor-domain ATPase activity. These findings contradict the attributed claim that 100 μM ciliobrevin D inhibited both motors. (LLM, conf=0.93)

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References 30 · Cited by 403

Research works printed but not linked: 30

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Authors
Firestone, A. J., Weinger, J. S., Maldonado, M., Barlan, K., Langston, L. D., O’Donnell, M., Gelfand, V. I., Kapoor, T. M., & Chen, J. K.
Affiliations
  • Stanford Medicine (US)
  • Rockefeller University (US)
  • Northwestern University (US)
Corresponding author
  • Kapoor, Tarun M.
  • Chen, James K.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2012-03-18
Volume
484
Issue
7392
Pages
125-129
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature10936
PMC
PMC3321072
OpenAlex
W2027415486
Cited by
403
References
30
Citations by year
2026: 26 · 2025: 21 · 2024: 23 · 2023: 18 · 2022: 28 · 2021: 25 · 2020: 33 · 2019: 31 · 2018: 33 · 2017: 34 · 2016: 22 · 2015: 43 · 2014: 35 · 2013: 23 · 2012: 8
FWCI
21.01
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA136574)
  • National Institute of General Medical Sciences (R01GM52111, R01GM052111, R01GM038839, R01GM065933, R01-GM65933, R01 GM71772, R24GM071772)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
Keywords
cytoplasmic dynein, AAA+ ATPase, small molecule inhibitors, microtubule motor proteins, primary cilia, Hedgehog signaling, mitotic spindle formation, kinetochore-microtubule attachment, melanosome transport, organelle transport, ATPase inhibition, microtubule gliding
MeSH terms
Animals, Cattle, Cilia, Cytoplasm, Enzyme Inhibitors, Microtubules, Spindle Apparatus, Molecular Weight, Movement, Signal Transduction, Kinetochores, Melanosomes, Peroxisomes, Protein Transport, NIH 3T3 Cells, Mice, Kruppel-Like Transcription Factors, Quinazolinones, Hedgehog Proteins, Cytoplasmic Dyneins

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