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Cytoplasmic Dynein Antagonists with Improved Potency and Isoform Selectivity
journal contribution
posted on 2016-01-15, 12:05 authored by Stephanie
K. See, Sascha Hoogendoorn, Andrew H. Chung, Fan Ye, Jonathan
B. Steinman, Tomoyo Sakata-Kato, Rand M. Miller, Tommaso Cupido, Ruta Zalyte, Andrew
P. Carter, Maxence V. Nachury, Tarun M. Kapoor, James K. ChenCytoplasmic dyneins
1 and 2 are related members of the AAA+ superfamily
(ATPases associated with diverse cellular activities) that function
as the predominant minus-end-directed microtubule motors in eukaryotic
cells. Dynein 1 controls mitotic spindle assembly, organelle movement,
axonal transport, and other cytosolic, microtubule-guided processes,
whereas dynein 2 mediates retrograde trafficking within motile and
primary cilia. Small-molecule inhibitors are important tools for investigating
motor protein-dependent mechanisms, and ciliobrevins were recently
discovered as the first dynein-specific chemical antagonists. Here,
we demonstrate that ciliobrevins directly target the heavy chains
of both dynein isoforms and explore the structure–activity
landscape of these inhibitors in vitro and in cells.
In addition to identifying chemical motifs that are essential for
dynein blockade, we have discovered analogs with increased potency
and dynein 2 selectivity. These antagonists effectively disrupt Hedgehog
signaling, intraflagellar transport, and ciliogenesis, making them
useful probes of these and other cytoplasmic dynein 2-dependent cellular
processes.