ArticleCell chemical biology2021
Targeting allostery in the Dynein motor domain with small molecule inhibitors.
Article in Cell chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed, 6 citations in OpenAlex.
- Application of temperature replica exchange molecular dynamics: Structure of mitotic spindle-associated protein SHE1 and its binding to dynein.Computational and structural biotechnology journal · 2025Article
- Cargo specificity, regulation, and therapeutic potential of cytoplasmic dynein.Experimental & molecular medicine · 2024Review
- Role of motor proteins in human cancers.Saudi journal of biological sciences · 2022Review
- Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical "Toolkit".International journal of molecular sciences · 2021Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.