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Structure of spastin AAA domain in complex with a quinazoline-based inhibitorStructure of spastin AAA domain in complex with a quinazoline-based inhibitor
Structural highlights
FunctionSPAST_DROME ATP-dependent microtubule severing protein. Stimulates microtubule minus-end depolymerization and poleward microtubule flux in the mitotic spindle. Regulates microtubule stability in the neuromuscular junction synapse.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedThe 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 AAA (ATPases Associated with diverse cellular Activities) superfamily, we lack the structural data needed for the design of 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 char-acterize the residues involved in inhibitor binding. We show that an inhibitor analog with a single atom hydro-gen-to-fluorine modification can selectively target a spastin allele with an engineered cysteine mutation in its active site. We also report a x-ray structure of the fluoro-analog bound to the spastin mutant, along with analyses of other alleles with mutations at this position, that re-veal how stereoelectronics of the fluorine-cysteine inter-action, rather than sterics alone, contribute to inhibitor-allele selectivity. This approach could be used to design allele-specific probes for studying cellular functions of spastin isoforms. Our data suggests how tuning stereoe-lectronics can lead to specific inhibitor-allele pairs for the AAA superfamily. Designing Allele-Specific Inhibitors of Spastin, a Microtubule-Severing AAA Protein.,Pisa R, Cupido T, Kapoor TM J Am Chem Soc. 2019 Mar 15. doi: 10.1021/jacs.8b13257. PMID:30875216[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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