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PDBsum entry 5ogc
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Transport protein
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PDB id
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5ogc
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Contents |
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328 a.a.
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412 a.a.
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426 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural basis of human kinesin-8 function and inhibition.
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Authors
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J.Locke,
A.P.Joseph,
A.Peña,
M.M.Möckel,
T.U.Mayer,
M.Topf,
C.A.Moores.
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Ref.
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Proc Natl Acad Sci U S A, 2017,
114,
E9539.
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PubMed id
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Abstract
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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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