Laboratory of Dr. Sunyoung Kim
PhD, University of Michigan at Ann Arbor, 1994

From Left: Rebecca Buckley Jessica Richard, Dr. Sunyoung Kim and Bokkyoo Jun

A suite of biochemical, molecular, and biophysical tools are used to probe members of two protein families: (1) the Kinesin-5 motor family toward dissecting the selective impact of allosteric compounds on proteins with accepted roles in powering cell division, and (2) photolyase/cryptochrome family in answering how the protein matrix can control communication among redox-active species and developing biological tools to prevent skin cancer.

The Kinesin-5 protein family The evolution of small-molecule sensitivity in the Kinesin-5 subfamily of motor proteins involved in cell division. Inhibition of mitosis is at the crux of clinical strategies to control tumor growth. Required for normal spindle function in higher eukaryotes, the protein Eg5 is thought to crosslink antiparallel microtubules, and provides a force required for the formation of a bipolar spindle. Inhibition of Eg5 by allosteric inhibitors leads to mitotic arrest in normal and tumor cell lines, yielding cells with a monoastral spindle. The archetype small-molecule inhibitor of Eg5 is monastrol, a dihydropyrimidine derivative, and its discovery has unleashed reports of other potential anticancer agents. Highlighted is the fact that these compounds do not affect other kinesin family members. Thus, not only does inhibition of Eg5 provide a novel and specific mechanism to target the mitotic spindle, but also homologs of Eg5 provide biological venues in which the sequence determinants for specificity of productive drug response can be monitored and manipulated. Due to its therapeutic potential in clinical settings, there is keen interest in understanding the mechanism by which monastrol hampers mechanotransduction in Eg5. Further dissection of the mechanism of allosteric inhibition by monastrol on Eg5 is crucial to clarifying its potential as an anti-cancer agent and to establish a blueprint for the development of other candidate anticancer drugs. With the Wojcik and Walker laboratories, we have established an interdisciplinary approach to understanding the mechanistic details toward allosteric regulation of an important player in the mitotic machinery.

Photolyase/cryptochrome family Controlling communication among redox-active species in the protein matrix. Dependent upon the presence of adjacent pyrimidine bases, the cis-syn cyclobutylpyrimidine dimer (CPD) is the major photoproduct induced by UV light. These photoproducts are removed by DNA repair systems to minimize deleterious genetic effects, including mutation and skin cancer. Photolyase is a unique repair enzyme that catalytically reverses the cis-syn cyclobutane pyrimidine dimers, by using light energy to initiate a series of electron-proton transfer reactions from its flavin cofactor. Despite broad structural and mechanistic similarities, the photolyase homologue, cryptochrome, does not exhibit DNA repair activity; instead, it utilizes light energy for its roles in signal transduction and entrainment of circadian clocks. Our focus is to map the molecular interactions by which photolyase/cryptochrome protein family copes with reactive radical intermediates generated via proton and electron transfer pathways. A distinct advantage of our experimental methods derives from the exquisite sensitivity in measuring changes in molecular bonds and changes in distribution of total electron density that occur during electron transfer events. Three ongoing experimental tracks are establishment of the requirement and nature of intermediates for efficient electron transfer, modulation of amino acid radical formation in peptides by primary sequence, and constraints for protein-substrate interaction for photolyase and protein-protein interactions for cryptochrome signal transduction.

Recent Publications

Learman SS, Kim CD, Stevens NS, Kim S, Wojcik EJ, Walker RA. NSC 622124 Inhibits Human Eg5 and Other Kinesins via Interaction with the Conserved Microtubule-Binding Site (dagger). Biochemistry. Mar 3;48(8):1754-1762.(2009)

Wojcik, E.J., Dalrymple, N.A., Alford, S.R., Walker, R.A., and Kim, S., Disparity in allosteric interactions of monastrol with Eg5 in the presence of ADP and ATP: a difference FT-IR investigation, Biochemistry, 43, (2004)

Kim, S., Sacksteder, C., Bixby, K., and Barry, B.A., A reaction-induced FT-IR study of cyanobacterial photosystem I, Biochemistry, 50 (2001)

Kim, S., and Barry, B.A., Reaction-induced FT-IR spectroscopic studies of biological energy conversion in oxygenic photosynthesis and transport, Journal of Physical Chemistry (invited feature article with cover) B 105, (2001)

Kim, S., Patzlaff, J.P., Krick, T., Ayala, I., Sachs, R., and Barry, B.A., Isotope-based discrimination between the infrared modes of plastosemiquinone anion radicals and neutral tyrosyl radicals in photosystem II, Journal of Physical Chemistry B 104 (2000)

Kim, S., and Barry, B.A., Identification of carbonyl modes of P700 and P700+ by in situ chlorophyll labeling in photosystem I, Journal of the American Chemical Society 122 (2000)

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