Crystal structure of human fidgetin-like protein 1 in complex with ADP

Karlberg, T.; Wiśniewska, M.; Andersson, Jan; Arrowsmith, C.H.; Berglund, H.; Busam, R.D.; Collins, R.; Dahlgren, Lars; Edwards, A.M.; Flodin, S.; Flores, A.; Gräslund, S.; Hammarstrom, M.; Johansson, A.; Johansson, I.; Kallas, Å.; Kotenyova, T.; Lehtiö, L.; Moche, M.; Nilsson, M.E.; Nordlund, P.; Nyman, T.; Olesen, Kenneth; Persson, Christer; Sagemark, J.; Thorsell, A.G.; Tresaugues, L.; Berg, S. Van Den; Welin, M.; Wikström, Mats; Schüler, H.

doi:10.2210/pdb3d8b/pdb

2008

DOI: 10.2210/pdb3d8b/pdb

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Crystal structure of human fidgetin-like protein 1 in complex with ADP

T. Karlberg¹,

M. Wiśniewska²,

Jan Andersson³

et al.

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Crystal structure of the human spastin AAA domain

Taylor

White

Lauring

et al. 2012

Journal of Structural Biology

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Hereditary spastic paraplegia (HSP) is a motor neuron disease caused by a progressive degeneration of the motor axons of the corticospinal tract. Point mutations or exon deletions in the microtubule-severing ATPase, spastin, are responsible for approximately 40% of cases of autosomal dominant HSP. Here, we report the 3.3 Å X-ray crystal structure of a hydrolysis- deficient mutant (E442Q) of the human spastin protein AAA domain. This structure is analyzed in the context of the existing Drosophila melanogaster spastin AAA domain structure and crystal structures of other closely related proteins in order to build a more unifying framework for understanding the structural features of this group of microtubule-severing ATPases.

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Crystal structure of the human spastin AAA domain

Taylor

White

Lauring

et al. 2012

Journal of Structural Biology

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Designing a chemical inhibitor for the AAA protein spastin using active site mutations

et al. 2019

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Spastin is a microtubule-severing AAA (ATPases associated with diverse cellular activities) protein needed for cell division and intracellular vesicle transport. Currently, we lack chemical inhibitors to probe spastin function in such dynamic cellular processes. To design a chemical inhibitor of spastin we tested selected heterocyclic-scaffolds against wildtype protein and constructs with engineered mutations in the nucleotide-binding site that do not substantially disrupt ATPase activity. These data, along with computational docking, guided improvements in compound potency and selectivity and led to spastazoline, a pyrazolyl-pyrrolopyrimidine-based cell-permeable probe for spastin. These studies also identified spastazoline resistance-conferring point mutations in spastin. Spastazoline, along with matched inhibitor-sensitive and inhibitor-resistant cell lines we generated, were used in parallel experiments to dissect spastin-specific phenotypes in dividing cells. Together, our findings suggest how chemical probes for AAA proteins, along with inhibitor resistance-conferring mutations, can be designed and used to dissect dynamic cellular processes.

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Crystal structure of human fidgetin-like protein 1 in complex with ADP

Cited by 2 publications

References 0 publications

Crystal structure of the human spastin AAA domain

Crystal structure of the human spastin AAA domain

Designing a chemical inhibitor for the AAA protein spastin using active site mutations

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