| Structural highlights
Function
SPAST_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 PubMed
Drug-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
- ↑ Trotta N, Orso G, Rossetto MG, Daga A, Broadie K. The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Curr Biol. 2004 Jul 13;14(13):1135-47. PMID:15242610 doi:https://dx.doi.org/10.1016/j.cub.2004.06.058
- ↑ Sherwood NT, Sun Q, Xue M, Zhang B, Zinn K. Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function. PLoS Biol. 2004 Dec;2(12):e429. Epub 2004 Nov 30. PMID:15562320 doi:https://dx.doi.org/10.1371/journal.pbio.0020429
- ↑ Roll-Mecak A, Vale RD. The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules. Curr Biol. 2005 Apr 12;15(7):650-5. PMID:15823537 doi:https://dx.doi.org/S0960-9822(05)00170-3
- ↑ Orso G, Martinuzzi A, Rossetto MG, Sartori E, Feany M, Daga A. Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. J Clin Invest. 2005 Nov;115(11):3026-34. PMID:16276413 doi:https://dx.doi.org/10.1172/JCI24694
- ↑ Zhang D, Rogers GC, Buster DW, Sharp DJ. Three microtubule severing enzymes contribute to the "Pacman-flux" machinery that moves chromosomes. J Cell Biol. 2007 Apr 23;177(2):231-42. PMID:17452528 doi:https://dx.doi.org/jcb.200612011
- ↑ Lee M, Paik SK, Lee MJ, Kim YJ, Kim S, Nahm M, Oh SJ, Kim HM, Yim J, Lee CJ, Bae YC, Lee S. Drosophila Atlastin regulates the stability of muscle microtubules and is required for synapse development. Dev Biol. 2009 Jun 15;330(2):250-62. doi: 10.1016/j.ydbio.2009.03.019. Epub 2009 , Mar 31. PMID:19341724 doi:https://dx.doi.org/10.1016/j.ydbio.2009.03.019
- ↑ Roll-Mecak A, Vale RD. Structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin. Nature. 2008 Jan 17;451(7176):363-7. PMID:18202664 doi:10.1038/nature06482
- ↑ Pisa R, Cupido T, Steinman JB, Jones NH, Kapoor TM. Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins. Cell Chem Biol. 2019 Jun 26. pii: S2451-9456(19)30182-5. doi:, 10.1016/j.chembiol.2019.06.001. PMID:31257183 doi:https://dx.doi.org/10.1016/j.chembiol.2019.06.001
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