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The structure of the ternary Eg5-ADP-ispinesib complex

S K Talapatra1, A W Schüttelkopf, F Kozielski

  • 1Molecular Motor Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, Scotland, UK. s.talapatra@beatson.gla.ac.uk

Acta Crystallographica. Section D, Biological Crystallography
|September 21, 2012
PubMed

Insights

Researchers determined the crystal structure of the kinesin Eg5 motor domain bound to the cancer drug ispinesib. This provides structural insights into Eg5 inhibition for potential cancer therapies.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • The human kinesin Eg5 is crucial for forming bipolar spindles during mitosis.
  • Eg5 inhibition leads to mitotic arrest and apoptosis, making it a promising cancer drug target.
  • Ispinesib is an advanced Eg5-targeting agent with demonstrated antitumor activity, currently in Phase II clinical trials.

Purpose of the Study:

  • To determine the crystal structure of the Eg5 motor domain in complex with the inhibitor ispinesib.
  • To elucidate the binding interactions between Eg5 and ispinesib at an atomic level.
  • To provide structural insights that can aid in the development of novel Eg5-targeting cancer therapeutics.

Main Methods:

  • X-ray crystallography was used to determine the structure of the Eg5-ispinesib complex.
  • Kinetic and thermodynamic binding assays were performed to characterize the interaction.
  • Advanced data processing and refinement techniques were employed to overcome crystallographic challenges.

Main Results:

  • The crystal structure of the Eg5 motor domain bound to ispinesib was determined.
  • Ispinesib was found to bind in an induced-fit pocket, forming extensive hydrophobic interactions with Eg5.
  • The study addressed and overcame challenges related to pseudo-merohedral twinning and non-crystallographic symmetry.

Conclusions:

  • The determined structure provides a detailed atomic view of Eg5 inhibition by ispinesib.
  • These findings offer valuable structural information for the rational design of future Eg5 inhibitors.
  • The study overcomes previous limitations in structural data for Eg5-targeting agents.

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