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Targeting allostery in the Dynein motor domain with small molecule inhibitors.
Santarossa, Cristina C; Mickolajczyk, Keith J; Steinman, Jonathan B; Urnavicius, Linas; Chen, Nan; Hirata, Yasuhiro; Fukase, Yoshiyuki; Coudray, Nicolas; Ekiert, Damian C; Bhabha, Gira; Kapoor, Tarun M.
Afiliación
  • Santarossa CC; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA; Tri-Institutional PhD program in Chemical Biology, The Rockefeller University, New York, NY 10065, USA.
  • Mickolajczyk KJ; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
  • Steinman JB; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
  • Urnavicius L; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
  • Chen N; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
  • Hirata Y; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065, USA.
  • Fukase Y; Tri-Institutional Therapeutics Discovery Institute, New York, NY 10065, USA.
  • Coudray N; Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY 10016, USA.
  • Ekiert DC; Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
  • Bhabha G; Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA. Electronic address: gira.bhabha@gmail.com.
  • Kapoor TM; Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: kapoor@rockefeller.edu.
Cell Chem Biol ; 28(10): 1460-1473.e15, 2021 10 21.
Article en En | MEDLINE | ID: mdl-34015309
Cytoplasmic dyneins are AAA (ATPase associated with diverse cellular activities) motor proteins responsible for microtubule minus-end-directed intracellular transport. Dynein's unusually large size, four distinct nucleotide-binding sites, and conformational dynamics pose challenges for the design of potent and selective chemical inhibitors. Here we use structural approaches to develop a model for the inhibition of a well-characterized S. cerevisiae dynein construct by pyrazolo-pyrimidinone-based compounds. These data, along with functional assays of dynein motility and mutagenesis studies, suggest that the compounds inhibit dynein by engaging the regulatory ATPase sites in the AAA3 and AAA4 domains, and not by interacting with dynein's main catalytic site in the AAA1 domain. A double Walker B mutation of the AAA3 and AAA4 sites substantially reduces enzyme activity, suggesting that targeting these regulatory domains is sufficient to inhibit dynein. Our findings reveal how chemical inhibitors can be designed to disrupt allosteric communication across dynein's AAA domains.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dineínas / Proteínas de Saccharomyces cerevisiae / Bibliotecas de Moléculas Pequeñas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dineínas / Proteínas de Saccharomyces cerevisiae / Bibliotecas de Moléculas Pequeñas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos