Cytoplasmic Dynein Antagonists with Improved Potency and Isoform Selectivity
| Autor: | Ruta Zalyte, Maxence V. Nachury, Andrew P. Carter, Rand M. Miller, Fan Ye, Tommaso Cupido, Jonathan B. Steinman, Andrew H. Chung, Tarun M. Kapoor, Sascha Hoogendoorn, Stephanie K. See, Tomoyo Sakata-Kato, James K. Chen |
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| Rok vydání: | 2015 |
| Předmět: |
Cytoplasmic Dyneins
0301 basic medicine Dynein macromolecular substances Biology Biochemistry Substrate Specificity Mice Structure-Activity Relationship 03 medical and health sciences Microtubule Animals Protein Isoforms Structure–activity relationship Hedgehog Proteins Letters Quinazolinones Molecular Structure Cilium General Medicine AAA proteins Cell biology 030104 developmental biology NIH 3T3 Cells Dynactin Axoplasmic transport Molecular Medicine Signal Transduction |
| Zdroj: | See, SK; Hoogendoorn, S; Chung, AH; Ye, F; Steinman, JB; Sakata-Kato, T; et al.(2016). Cytoplasmic Dynein Antagonists with Improved Potency and Isoform Selectivity. ACS CHEMICAL BIOLOGY, 11(1), 53-60. doi: 10.1021/acschembio.5b00895. UCSF: Retrieved from: http://www.escholarship.org/uc/item/3tn1x71x ACS Chemical Biology |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.5b00895 |
| Popis: | Cytoplasmic 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. |
| Databáze: | OpenAIRE |
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