Abstract
Kinesin microtubule motor proteins play essential roles in division, including attaching chromosomes to spindles and crosslinking microtubules for spindle assembly. Human kinesin-14 KIFC1 is unique in that cancer cells with amplified centrosomes are dependent on the motor for viable division because of its ability to cluster centrosomes and form bipolar spindles, but it is not required for division in almost all normal cells. Screens for small molecule inhibitors of KIFC1 have yielded several candidates for further development, but obtaining structural data to determine their sites of binding has been difficult. Here we compare a previously unreported KIFC1 crystal structure with new structures of two closely related kinesin-14 proteins, Ncd and KIFC3, to determine the potential binding site of a known KIFC1 ATPase inhibitor, AZ82. We analyze the previously identified kinesin inhibitor binding sites and identify features of AZ82 that favor binding to one of the sites, the α4/α6 site. This selectivity can be explained by unique structural features of the KIFC1 α4/α6 binding site. These features may help improve the drug-like properties of AZ82 and other specific KIFC1 inhibitors.
Highlights
Kinesin motor proteins hydrolyze ATP to produce force and do work in cells
The KIFC1, KIFC3 and Ncd proteins that we analyzed are shown in Fig. 1A, together with a kinesin-14 family tree (Fig. 1B)
Measurement of branch lengths in the tree indicates that KIFC1 is more closely related to Ncd (326 changes) than KIFC3 (346 changes)
Summary
Hee-Won Park[1,8], Zhujun Ma2,3, Haizhong Zhu[1,9], Shimin Jiang[4,5,10], Robert C. Their study has produced new information about the mechanism by which the motors function Despite their diverse functions, the kinesin proteins contain a common motor domain with highly conserved or invariant sequence motifs that mediate basic motor properties, such as microtubule binding and ATP hydrolysis. Crystal structures show that the kinesin motor domain is highly conserved[16,17], despite basic differences among kinesins in directionality and processivity, as well as force generation[8,18] Their essential roles in mitosis raise the possibility that targeting specific kinesins could inhibit or block the unregulated division associated with cancers, providing new targets for treatment. The structural differences we observe between KIFC1 and its homologues, KIFC3 and Ncd, and between the two heads of Ncd, which are thought to represent different states of the motor, allow us to reach conclusions regarding the likely binding site of AZ82 in KIFC1
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