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A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors
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Structural basis of small molecule ATPase inhibition of a human mitotic kinesin motor protein

Hee-Won Park1,2, Zhujun Ma3,4, Haizhong Zhu1,5

  • 1Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.

Scientific Reports
|November 11, 2017
PubMed

Insights

Human kinesin-14 KIFC1 is crucial for cancer cell division. Researchers identified a specific binding site for the inhibitor AZ82 by comparing KIFC1 structures, aiding drug development.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • Kinesin motor proteins, particularly kinesin-14 family members, are vital for cell division processes like chromosome attachment and spindle assembly.
  • Human kinesin-14 KIFC1 is essential for the division of cancer cells with amplified centrosomes, but not for normal cell division.
  • Developing small molecule inhibitors for KIFC1 presents challenges due to difficulties in obtaining structural data for binding site identification.

Purpose of the Study:

  • To determine the potential binding site of the KIFC1 ATPase inhibitor AZ82.
  • To elucidate the structural basis for AZ82's selectivity towards KIFC1.
  • To inform the development of improved KIFC1-specific inhibitors for cancer therapy.

Main Methods:

  • Comparative structural analysis of a new KIFC1 crystal structure with related kinesin-14 proteins (Ncd and KIFC3).
  • Analysis of previously identified kinesin inhibitor binding sites.
  • Structure-based investigation of AZ82 binding interactions within KIFC1.

Main Results:

  • A previously unreported KIFC1 crystal structure was determined and compared with Ncd and KIFC3 structures.
  • The study identified the α4/α6 site as the favored binding location for the KIFC1 inhibitor AZ82.
  • Unique structural features of the KIFC1 α4/α6 site explain the selectivity of AZ82 binding.

Conclusions:

  • The structural insights gained provide a basis for understanding AZ82's specific interaction with KIFC1.
  • These findings can guide the optimization of AZ82 and the design of novel KIFC1 inhibitors with enhanced drug-like properties.
  • Targeting KIFC1 offers a promising strategy for cancer treatment, particularly in cancers dependent on this motor protein for division.

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