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- W2914697001 abstract "Kinesin superfamily members use ATP to drive mechanical output on the microtubule cytoskeleton. This mechanochemical behaviour has been specialised in the different kinesin families, and also between species. It has also been hypothesised that such differences could permit kinesin family, and even species specific inhibition by small-molecules. This triggered our structural and biochemical studies on the kinesin-5 family member from the malaria causing parasite – Plasmodium falciparum Kinesin-5 (PfK5). From this data we aimed to gain insight into the key aspects of kinesin mechanochemistry, and how this motor function may be adapted between species. In addition, we explored whether these adaptions can be exploited for the development of species specific inhibition of kinesin-5s - potentially opening the door to new anti-malarial therapeutics. To do this we employed single particle cryo-electron microscopy to visualize PfK5 in nucleotide-free and ATP-like stages of its mechanochemical cycle bound to microtubules. We used new techniques in 3D image processing and molecular modelling to obtain a near-atomic representation of PfK5's mechanochemical cycle. In conjunction with studies on PfK5's steady state ATP activity, and single molecule microtubule binding using total internal reflection microscopy, we have described PfK5 molecular properties. We find that PfK5 exhibits nucleotide dependent conformational changes and biochemical behaviour that are characteristic of a kinesin-5 family member. Conversely, we also observe evidence of some atypical biochemical properties which are explained by several unexpected conformations seen in our 3D reconstructions. Strikingly, a Plasmodium species specific insertion radically alters the chemical environment of the kinesin drug binding site, offering the possibility of PfK5-specific inhibition. Our results broaden our understanding of how evolution adapts the core function of eukaryotic kinesin mechanochemistry, and how we may utilise these differences in therapeutic development." @default.
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- W2914697001 date "2019-02-01" @default.
- W2914697001 modified "2023-09-30" @default.
- W2914697001 title "The Cryo-EM Structure and Activity of Kinesin-5 from Plasmodium falciparum: Mechanistic Lessons from a Parasite Kinesin" @default.
- W2914697001 doi "https://doi.org/10.1016/j.bpj.2018.11.1671" @default.
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