Aplysqualenol A Binds to the Light Chain of Dynein Type 1 (DYNLL1).
ABSTRACT A bidirectional affinity system has been developed for the identification of cancer-related natural products and their biological targets. Aplysqualenol A is thus selectively identified as a ligand of the dynein light chain. The use of forward and reverse affinity methods suggests that both small-molecule isolation and target identification can be conducted using conventional molecular biological methods.
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ABSTRACT: Cytoplasmic dynein plays important roles in membrane transport, mitosis, and other cellular processes. A few small-molecule inhibitors of cytoplasmic dynein have been identified. We report here the first synthesis of purealin, a natural product isolated from the sea sponge Psammaplysilla purea, which is known to inhibit axonemal dynein. Also described are the first syntheses, by modular amide coupling reactions, of the natural product purealidin A (a component of purealin) and a small library of analogues. The library was examined for inhibition of cytoplasmic dynein heavy chain and cell growth. The compounds showed effective antiproliferative activity against a mouse leukemia cell line but selective activities against human carcinoma cell lines. Purealin and some of the analogues inhibited the microtubule-stimulated ATPase activity of recombinant cytoplasmic dynein heavy chain motor domain. The inhibitory effect of purealin was concentration dependent and uncompetitive, supporting the hypothesis that it does not compete with the binding of ATP.Journal of Medicinal Chemistry 04/2006; 49(6):2063-76. · 5.61 Impact Factor
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ABSTRACT: Several recent studies have highlighted the role of axonal transport in the pathogenesis of motor neuron diseases. Mutations in genes that control microtubule regulation and dynamics have been shown to cause motor neuron degeneration in mice and in a form of human motor neuron disease. In addition, mutations in the molecular motors dynein and kinesins and several proteins associated with the membranes of intracellular vesicles that undergo transport cause motor neuron degeneration in humans and mice. Paradoxically, evidence from studies on the legs at odd angles (Loa) mouse and a transgenic mouse model for human motor neuron disease suggest that partial limitation of the function of dynein may in fact lead to improved axonal transport in the transgenic mouse, leading to delayed disease onset and increased life span.Journal of Neuroscience Research 10/2007; 85(12):2557-66. · 2.97 Impact Factor
Article: The molecular anatomy of dynein.[show abstract] [hide abstract]
ABSTRACT: Recent molecular, genetic and functional studies have led to an unparalleled growth in our understanding of dynein and the roles played by the various polypeptides of these massive macromolecular assemblies. Dyneins are highly complex 1-2MDa complexes that function as molecular motor and move the cargo to which they are attached towards the minus-end of a microtubule. Dynein motor function is a property of the heavy chains, whereas the intermediate chains are involved in attachment to the appropriate cargo. In order for useful work to be obtained, motor and cargo-binding activities must be tightly controlled. Current data suggest that this is the role played by certain accessory light-chain proteins. The LC8 is highly conserved and found in many enzyme systems. This protein is essential in multicellular organisms. The dynein light chains Tctex1 and Tctex2 have been implicated in the non-Mendelian transmission of variant forms of mouse chromosome 17.Essays in Biochemistry 02/2000; 35:75-87. · 3.47 Impact Factor