SummaryKinesin-5s are essential members of the superfamily of microtubule-dependent motors that undertake conserved roles in cell division. We investigated coevolution of the motor-microtubule interface using cryo-electron microscopy to determine the near-atomic structure of the motor domain of Cut7, the fission yeast kinesin-5, bound to fission yeast microtubules. AMPPNP-bound Cut7 adopts a kinesin-conserved ATP-like conformation, with a closed nucleotide binding pocket and docked neck linker that supports cover neck bundle formation. Compared to mammalian tubulin microtubules, Cut7’s footprint onS. pombemicrotubule surface is subtly different because of their different architecture. However, the core motor-microtubule interaction that stimulates motor ATPase is tightly conserved, reflected in similar Cut7 ATPase activities on each microtubule type. TheS. pombemicrotubules were bound by the drug epothilone, which is visible in the taxane binding pocket. Stabilization ofS. pombemicrotubules is mediated by drug binding at this conserved site despite their noncanonical architecture and mechanochemistry.HighlightsS. pombeCut7 has a distinct binding footprint onS. pombemicrotubulesThe core interface driving microtubule activation of motor ATPase is conservedThe neck linker is docked in AMPPNP-bound Cut7 and the cover neck bundle is formedEpothilone binds at the taxane binding site to stabilizeS. pombemicrotubuleseTOC textTo investigate coevolution of the motor-microtubule interface, we used cryo-electron microscopy to determine the near-atomic structure of the motor domain of Cut7, the fission yeast kinesin-5, bound to microtubules polymerized from natively purified fission yeast tubulin and stabilised by the drug epothilone.