Kinesin is a motor protein of the cell. Members of the kinesin superfamily of proteins are responsible for vital functions such as vessicle transport, chromosome segregation. Kinesin proteins bind and hydrolyze ATP whilst attached to microtubules, fairly rigid polymers of proteins that make up the cytoskeleton of the cell. The coupling of the chemical energy to produce directed force and movement is one of the fundamental processes in biology. This chemomechanical coupling is still not understood in the context of the detailed molecular structure described for two kinesin family-members: human kinesin and ncd, a related motor that moves in the opposite direction along the microtubules. Methods of understanding kinesin function rely on measuring the altered motor function after site-directed mutagenesis. My approach to understanding kinesing function is to calculate a binding interaction between various small organic molecules and kinesin, with the goal of finding a compound to inhibit or otherwise alter kinesin's function under the influence of the bound molecule. I am using UCSF Dock to screen a database of available chemicals, and test a selection of compounds predicted to bind. This selection relies on the facilities of the Computer Graphics Laboratory to view the bound molecule in three-dimensions with computer graphics. Out of the 90 or so compounds bought and tested so far, about 24 of these are sub-millimolar inhibitors of kinesin ATPase. Further calculations and interactive molecular graphics will be needed to discern the modes of binding and find similar but possibly more active compounds. Finally, compounds found to inhibit kinesin may prove useful for further study in cellular processes and disease states.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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