6p14
Structure of spastin AAA domain (T692A mutant) in complex with a diaminotriazole-based inhibitor (crystal form B)Structure of spastin AAA domain (T692A mutant) in complex with a diaminotriazole-based inhibitor (crystal form B)
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 PubMedDrug-like inhibitors are often designed by mimicking cofactor or substrate interactions with enzymes. However, as active sites are comprised of conserved residues, it is difficult to identify the critical interactions needed to design selective inhibitors. We are developing an approach, named RADD (resistance analysis during design), which involves engineering point mutations in the target to generate active alleles and testing compounds against them. Mutations that alter compound potency identify residues that make key interactions with the inhibitor and predict target-binding poses. Here, we apply this approach to analyze how diaminotriazole-based inhibitors bind spastin, a microtubule-severing AAA (ATPase associated with diverse cellular activities) protein. The distinct binding poses predicted for two similar inhibitors were confirmed by a series of X-ray structures. Importantly, our approach not only reveals how selective inhibition of the target can be achieved but also identifies resistance-conferring mutations at the early stages of the design process. Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.,Pisa R, Cupido T, Steinman JB, Jones NH, Kapoor TM Cell Chem Biol. 2019 Jun 26. pii: S2451-9456(19)30182-5. doi:, 10.1016/j.chembiol.2019.06.001. PMID:31257183[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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