5OCU

Molecular basis of human kinesin-8 function and inhibition

Summary for 5OCU

• Entry DOI: 10.2210/pdb5ocu/pdb
• Related: 5oam 5ogc
• EMDB information: 3778 3780 3803
• Descriptor: Kinesin-like protein KIF18A, Tubulin alpha chain, Tubulin beta chain, ... (9 entities in total)
• Functional Keywords: cytoskeleton, motor protein, kinesin, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 144669.45

Authors

Locke, J.,Joseph, A.P.,Topf, M.,Moores, C.A. (deposition date: 2017-07-03, release date: 2017-10-25, Last modification date: 2024-05-15)

Primary citation

Locke, J.,Joseph, A.P.,Pena, A.,Mockel, M.M.,Mayer, T.U.,Topf, M.,Moores, C.A.
Structural basis of human kinesin-8 function and inhibition.
Proc. Natl. Acad. Sci. U.S.A., 114:E9539-E9548, 2017

PubMed 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.

PubMed: 29078367
DOI: 10.1073/pnas.1712169114

Experimental method

ELECTRON MICROSCOPY (5.2 Å)