Associate Professor, Fralin Biomedical Research Institute
Program Focus
The goal of our project is to advance the frontiers of biology, chemistry and nanometer-scale technology to better understand processes that lead to disease development, progression, and treatment. Our interdisciplinary group encompasses a broad spectrum of competence, ranging from pure chemistry and molecular biologists to several applied disciplines thus providing a unique opportunity to create a unified research program devoted to translational-based research.
Summary of Proposed Research Plan:The emerging field of chronotherapy, in which treatments for various diseases are administered at times of the day most likely to yield the greatest efficacy, will rely on deciphering the regulatory systems to which all circadian components connect, and most importantly, on understanding the structural complexity that determines the specificity of their interactions.
In recent years, a family of antidepressants, addictive drugs and antiproliferative agents (all known as “ligands”) were used to regulate the expression of therapeutically relevant circadian-controlled genes by directly targeting a key regulatory protein complex named Clock/Bmal1. However, there is no evidence of how binding specificity among these molecules is achieved in a biologically relevant setting nor structural characterization of pharmacologically-relevant inhibitor binding sites in the Clock/Bmal1 complex. Moreover, the strength (affinity) and mode of their association (i.e. cooperativity, one molecule helps the other one to bind) have not been explored, the regulatory mechanisms (what each protein does in the complex) are largely unknown, and correlations between in vitro specificity and in vivo selectivity (the ligand exclusively binds to one complex among the hundreds in the cell) remain elusive. We propose to use a multidisciplinary approach that includes x-ray crystallography, biophysical studies and in vivo analysis of complex-ligand interactions to address these fundamental problems. The long-term goal of this proposal is to use structural information of the circadian molecules-ligand complex to design modified small molecule ligands with improved potency, selectivity, specificity and stability properties over first generation drugs. To achieve this goal, we envision strong collaborative efforts with other laboratories on campus as well as partnership with biotech companies. By consolidating links with industrial partners, we will be able to optimize the transfer of new findings and technology from the research laboratory into opportunities for improvement therapeutic treatments through the use of nanodevices.
Selected Publications
Capelluto, D. G. S.; Zhao, X.; Lucas, A.; Lemkul, J. A.; Xiao, S.; Fu, X.; Sun, F.; Bevan, D. R.; Finkielstein, C. V. Biophysical and Molecular-Dynamics Studies of Phosphatidic Acid Binding by the Dvl-2 DEP Domain Biophysical Journal. 2014, 106, 1101-1111. DOI: 10.1016/j.bpj.2014.01.032
Gotoh, T.; Vila-Caballer, M.; Santos, C. S.; Liu, J.; Yang, J.; Finkielstein, C. V. The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells Mol.Biol. Cell. 2014. 25, 3081. DOI:10.1091.mbc.E14-05-0993
Gotoh, T.; Vila-Caballer, M.; Liu, J.; Schiffhauer, S.; Finkielstein, C. V. Association of the circadian factor Period 2 to p53 influences p53’s function in DNA-damage signaling Mol. Biol. Cell 2014, 26, 359. DOI: 10.1091/mbc.E14-05-09944
Lucas, A. T.; Fu, X.; Liu, J.; Brannon, M. K.; Yang, J.; Capelluto, D. G. S; Finkielstein. Ligand Binding Reveals a Role for Heme in Translationally-Controlled Tumor Protein Dimerization PLos ONE. 2014, 9, e112823. doi:10.1371/journal.pone.0112823