ArticleProceedings of the National Academy of Sciences of the United States of America2017
Structural basis of human kinesin-8 function and inhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 60 citations in OpenAlex.
- Orthosteric Molecular Glue Inhibits COP9 Signalosome with Substrate-Dependent Potency.bioRxiv : the preprint server for biology · 2025Article
- KIF18A inhibition: the next big player in the search for cancer therapeutics.Cancer metastasis reviews · 2024Review
- HURP regulates Kif18A recruitment and activity to synergistically control microtubule dynamics.Nature communications · 2024Article
- Maternal genetic variants in kinesin motor domains prematurely increase egg aneuploidy.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Molecular interplay between HURP and Kif18A in mitotic spindle regulation.Research square · 2024Article
- Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition.The EMBO journal · 2024Article
- ChemEM: Flexible Docking of Small Molecules in Cryo-EM Structures.Journal of medicinal chemistry · 2024Article
- Microtubule depolymerization contributes to spontaneous neurotransmitter release in vitro.Communications biology · 2023Article
- Importin α/β promote Kif18B microtubule association and enhance microtubule destabilization activity.Molecular biology of the cell · 2023Article
- Mechanochemical tuning of a kinesin motor essential for malaria parasite transmission.Nature communications · 2022Article
- Kinesin-8-specific loop-2 controls the dual activities of the motor domain according to tubulin protofilament shape.Nature communications · 2022Article
- Integrated bioinformatics analysis to identify key genes related to the prognosis of esophageal squamous cell carcinoma.Translational cancer research · 2021Article
- Structural snapshots of the kinesin-2 OSM-3 along its nucleotide cycle: implications for the ATP hydrolysis mechanism.FEBS open bio · 2021Article
- TEMPy2: a Python library with improved 3D electron microscopy density-fitting and validation workflows.Acta crystallographica. Section D, Structural biology · 2021Article
- Automated Modeling and Validation of Protein Complexes in Cryo-EM Maps.Methods in molecular biology (Clifton, N.J.) · 2021Review
- Synthetic biology approaches to dissecting linear motor protein function: towards the design and synthesis of artificial autonomous protein walkers.Biophysical reviews · 2020Review
- These motors were made for walking.Protein science : a publication of the Protein Society · 2020Review
- Identification of biomarkers in colon cancer based on bioinformatic analysis.Translational cancer research · 2020Article
- Review
- Comparing Cryo-EM Reconstructions and Validating Atomic Model Fit Using Difference Maps.Journal of chemical information and modeling · 2020Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Kinesin motors play diverse roles in mitosis and are targets for antimitotic drugs. The clinical significance of these motors emphasizes the importance of understanding the molecular basis of their function. Equally important, investigations into the modes of inhibition of these motors provide crucial information about their molecular mechanisms. Kif18A regulates spindle microtubules through its dual functionality, with microtubule-based stepping and regulation of microtubule dynamics. We investigated the mechanism of Kif18A and its inhibition by the small molecule BTB-1. The Kif18A motor domain drives ATP-dependent plus-end microtubule gliding, and undergoes conformational changes consistent with canonical mechanisms of plus-end-directed motility. The Kif18A motor domain also depolymerizes microtubule plus and minus ends. BTB-1 inhibits both of these microtubule-based Kif18A activities. A reconstruction of BTB-1-bound, microtubule-bound Kif18A, in combination with computational modeling, identified an allosteric BTB-1-binding site near loop5, where it blocks the ATP-dependent conformational changes that we characterized. Strikingly, BTB-1 binding is close to that of well-characterized Kif11 inhibitors that block tight microtubule binding, whereas BTB-1 traps Kif18A on the microtubule. Our work highlights a general mechanism of kinesin inhibition in which small-molecule binding near loop5 prevents a range of conformational changes, blocking motor function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.