Department of Medicinal Chemistry and Molecular Pharmacology Personnel - Chiwook Park
Specialization: System-wide Investigation of Protein Folding and Protein-Ligand Interactions
EducationB.S. - 1991 - Seoul National University
M.S. - 1993 - Seoul National University
Ph.D. - 2000 - University of Wisconsin-Madison
Postdoc. 2001-2005 - University of California, Berkeley
Research: System-wide Investigation of Protein Folding and Protein-Ligand Interactions
Proteins are dynamic molecules. Even under native conditions, they do not adopt a single static conformation. Rather, they access many different conformations in their native state ensemble. This native state ensemble includes small fluctuations around the native conformation, partially unfolded forms, and even globally unfolded forms. The distribution of these conformations and the kinetic barriers between the conformational states define the conformational energy landscapes of proteins. My research interest is investigating conformational energy landscapes of proteins and deciphering the relationship between the energetics of proteins and their biochemical functions, such as catalysis, signal transduction, and ligand binding. We use proteolysis as a major tool to probe protein structures and dynamics as well as conventional spectroscopic methods. We also use proteomics extensively for investigating energy landscapes of proteins on a system level.
Investigation of conformational energy landscape of proteins on a proteomic scale
With the advent of the postgenomic and proteomic era, we face new challenges and new opportunities in protein folding studies. Can we obtain information on the energetics and dynamics of proteins on a proteomic scale? Can we study the relationship between the energetics and function of proteins at a system level? To address these issues, we use proteolysis as a structural probe. Conventional biophysical approaches using spectroscopy and calorimetry allow us to study only one protein at a time. However, by using proteolysis and proteomics tools, we can study energetics of multitude of proteins in a proteome at the same time. Currently, we attempt to determine global stabilities and unfolding kinetics of proteins on a proteomic scale. This research will allow us to understand why some proteins are more stable than the others and how evolution has shaped the distribution of thermodynamic and kinetic stabilities of proteins in a proteome.
Identification of cellular drug targets by proteolysis
Energy landscapes of proteins are perturbed by interaction with drug molecules. By monitoring these changes on a proteomic scale using proteolysis, we can identify cellular targets interacting with drug molecules. The cellular targets of effective drugs are often unknown. Moreover, novel chemicals affecting cellular activities are discovered at a tremendous speed by chemical genetics. By knowing the cellular target, we can design better drugs based on the structure and screen other drug candidates in vitro. In addition, these drugs serve as research tools to control cellular functions of the target. The following diagram shows the concept of drug target identification using proteolysis.
Investigation of kinetic and thermodynamic stability of membrane proteins and ligand binding to G-protein coupled receptors
In spite of the functional importance of membrane proteins, they have not been favorite research subjects in research on protein energetics. Membrane proteins are hard to express and purify. Therefore, conventional biophysical studies of membrane proteins are quite challenging. Using proteolysis as a structural probe, we are making a breakthrough in membrane protein research. Currently we aim to determine thermodynamic and kinetic stabilities of endogenous membrane proteins in cells without purifying them. This research will enhance our understanding of membrane protein energetics and dynamics significantly. Also, by measuring the change in stability by ligand binding, we are developing quantitative non-radioactive ligand binding assays for G-protein coupled receptors. Because G-protein coupled receptors are prominent drug targets, the novel assay methods will have a great impact in drug discovery and pharmacological research.
Lab Members:Chen Chen (Graduate Student)
Nathan William Gardner (PULSe Graduate Student)
Youngil Chang, Jonathan P Schlebach, Ross A VerHeul, and Chiwook Park
Pei-Fen Liu and Chiwook Park
Jonathan P Schlebach, Zheng Cao, James U Bowie, and Chiwook Park
Zheng Cao, Jonathan P Schlebach, Chiwook Park, and James U Bowie
Pei-Fen Liu, Daisuke Kihara, and Chiwook Park
Jonathan P Schlebach, Moon-Soo Kim, Nathan H Joh, James U Bowie, and Chiwook Park
Youngil Chang and Chiwook Park
Pei-Fen Liu, Larisa Avramova, and Chiwook Park
This record was last updated on Aug 5, 2013 at 9:29 AM