Designing Allele-Specific Inhibitors of Spastin, a Microtubule-Severing AAA Protein.

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

SUBMITTER: Pisa R 

PROVIDER: S-EPMC6637947 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature