Nature online: March 18, 2012
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Nature online: March 18, 2012
Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein
Ari J. Firestone, Joshua S. Weinger, Maria Maldonado, Kari Barlan, Lance D. Langston, Michael O’Donnell, Vladimir I. Gelfand, Tarun M. Kapoor and James K. Chen
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.
