ArticleJournal of the American Chemical Society2019
Designing Allele-Specific Inhibitors of Spastin, a Microtubule-Severing AAA Protein.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 23 citations in OpenAlex.
- Discovery of the microtubule-severing protein as the target of antifungal compound heat-stable antifungal factor in Fusarium graminearum and rational design of novel inhibitors.Pest management science · 2026Article
- Measurements of neurite extension and nucleokinesis in an iPSC-derived model system following microtubule perturbation.Molecular biology of the cell · 2025Article
- Article
- Achieving the promise and avoiding the peril of chemical probes using genetics.Current opinion in structural biology · 2023Review
- Targeting allostery in the Dynein motor domain with small molecule inhibitors.Cell chemical biology · 2021Article
- AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors.European journal of medicinal chemistry · 2021Review
- A chemical genetics approach to examine the functions of AAA proteins.Nature structural & molecular biology · 2021Article
- A RADD approach to probing AAA+ protein function.Nature structural & molecular biology · 2021Article
- Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.Cell chemical biology · 2019Article
- Who Needs a Contractile Actomyosin Ring? The Plethora of Alternative Ways to Divide a Protozoan Parasite.Frontiers in cellular and infection microbiology · 2019Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The bump-hole approach is a powerful chemical biology strategy to specifically probe the functions of closely related proteins. However, for many protein families, such as the ATPases associated with diverse cellular activities (AAA), we lack structural data for inhibitor-protein complexes to design allele-specific chemical probes. Here we report the X-ray structure of a pyrazolylaminoquinazoline-based inhibitor bound to spastin, a microtubule-severing AAA protein, and characterize the residues involved in inhibitor binding. We show that an inhibitor analogue with a single-atom hydrogen-to-fluorine modification can selectively target a spastin allele with an engineered cysteine mutation in its active site. We also report an X-ray structure of the fluoro analogue bound to the spastin mutant. Furthermore, analyses of other mutant alleles suggest how the stereoelectronics of the fluorine-cysteine interaction, rather than sterics alone, contribute to the inhibitor-allele selectivity. This approach could be used to design allele-specific probes for studying cellular functions of spastin isoforms. Our data also suggest how tuning stereoelectronics can lead to specific inhibitor-allele pairs for the AAA superfamily.
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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.