Hee-Won Park Ph.D.

Principal Investigator, Cell Signaling and Metabolism

Dr. Park's laboratory studies metabolic processes that use chemical energy derived from ATP or GTP hydrolysis. We focus on understanding the structural basis using X-ray crystallography for the following systems:

Small GTPases and their regulators, including GTPases activating proteins (GAPs) and Guanine nucleotide exchange factor (GEFs)
Nucleoside monophosphate/diphosphate kinases and other non-protein kinases, and
Kinesin molecular motors

Dr. Park received his DVM from Seoul National University, South Korea and his Ph.D. from University of Texas Southwestern Medical Center at Dallas, Texas. He was a postdoctoral fellow at Duke University Medical Center.

General Area of Research

Dr. Park's laboratory studies the structural aspects of intracellular protein and membrane trafficking pathways. Functional vesicular trafficking is central to normal cellular physiology. Ras-like proteins from rat brains (Rabs) and ADP ribosylation factors (Arfs) are regulators of trafficking of proteins and membranes by acting as docking sites for an assembly of effecter molecules. Mutations in Rabs, Arfs and their associated regulatory proteins or effectors are implicated in causing numerous human diseases.

Rab and Arf GTPases function as molecular switches, cycling between the switched-on state (GTP-bound) and the switched-off state (GDP-bound). The GTPase-activating proteins (GAPs) stimulate GTP-hydrolysis activity and thus keep Rabs and Arfs in the switched-off state, whereas the guanine nucleotide exchange factors (GEFs) exchange GDP for GTP and thus activate Rabs and Arfs to the switched-on state. The Arf and Rab structures and their complexes with GAPs and GEFs are essential for a better understanding of the structural dynamics of intracellular trafficking. Furthermore, these structural analyses will provide unique therapeutic opportunities in developing strategies that target Rab and Arf GTPases and their regulatory proteins.

We are also interested in understanding kinesin molecular motor function. Kinesins play diverse roles in organelle transport, cell division, and cell movement. Kinesins use the chemical energy derived from ATP hydrolysis to generate force for movement along the microtubule. The mechanism by which kinesins capture the energy from ATP hydrolysis and convert it to force is unknown. The structural elements that undergo movement and the force-producing conformational changes of the kinesin motor must be identified in order to elucidate this mechanism. We solve the structures of human kinesins to understand these motor functions. Knowledge of the kinesin structures will allow the rational design of small molecules and the development of specific inhibitors of human kinesin motor family.

Finally, we study structure/function relationships of non-protein kinases that catalyze the phosphorylation of non-protein substrates. Mutations of the non-protein kinases have been implicated in many different human disease. Many human genes encode the non-protein kinases. The sequences between the non-protein kinases share no obvious sequence similarity although the cores of the available structures resemble the nucleotide-binding fold. We perform the structural analysis of each and every non-protein kinases to understand their structure/functional relationships. The resulting structures will provide an explanation for pathogenic mutations that are present in patients with non-protein kinase-defective diseases.

Publications

Search Pubmed for publications of Dr. Park.

Reference List:

Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW: Structural analysis of CYP2R1 in complex with vitamin D3. J.Mol.Biol. 2008, 380:95-106.

Senisterra GA, Soo HB, Park HW, Vedadi M: Application of high-throughput isothermal denaturation to assess protein stability and screen for ligands. J.Biomol.Screen. 2008, 13:337-342.

Tempel W, Tong Y, Dimov S, Bochkarev A, Park H: First crystallographic models of human TBC domains in the context of a family-wide structural analysis. Proteins 2008, 71:497-502.

Park HW: Structure determination of the motor domain of yeast kinesin kar3 by x-ray crystallography. Methods Mol.Biol. 2007, 392:199-211.

Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, Shen L, Park HW, Buck M: Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J.Biol.Chem. 2007, 282:37215-37224.

Tempel W, Rabeh WM, Bogan KL, Belenky P, Wojcik M, Seidle HF, Nedyalkova L, Yang T, Sauve AA, Park HW, Brenner C: Nicotinamide riboside kinase structures reveal new pathways to NAD+. PLoS.Biol. 2007, 5:e263.

Hong BS, Senisterra G, Rabeh WM, Vedadi M, Leonardi R, Zhang YM, Rock CO, Jackowski S, Park HW: Crystal structures of human pantothenate kinases. Insights into allosteric regulation and mutations linked to a neurodegeneration disorder. J.Biol.Chem. 2007, 282:27984-27993.

Shanmuganatham KK, Ravichandran M, Howe MM, Park HW: Crystallization and preliminary X-ray analysis of phage Mu activator protein C in a complex with promoter DNA. Acta Crystallogr.Sect.F.Struct.Biol.Cryst.Commun. 2007, 63:620-623.

Hong BS, Yun MK, Zhang YM, Chohnan S, Rock CO, White SW, Jackowski S, Park HW, Leonardi R: Prokaryotic type II and type III pantothenate kinases: The same monomer fold creates dimers with distinct catalytic properties. Structure. 2006, 14: 1251-1261.

Virga KG, Zhang YM, Leonardi R, Ivey RA, Hevener K, Park HW, Jackowski S, Rock CO, Lee RE: Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors. Bioorg.Med.Chem. 2006, 14:1007-1020.

Chu HM, Yun M, Anderson DE, Sage H, Park HW, Endow SA: Kar3 interaction with Cik1 alters motor structure and function. EMBO J. 2005, 24:3214-3223.

Ismail SA, Park HW: Structural analysis of human liver glyceraldehyde-3-phosphate dehydrogenase. Acta Crystallogr.D.Biol.Crystallogr. 2005, 61:1508-1513.

Aziz RK, Ismail SA, Park HW, Kotb M: Post-proteomic identification of a novel phage-encoded streptodornase, Sda1, in invasive M1T1 Streptococcus pyogenes. Mol.Microbiol. 2004, 54:184-197.

Brown VM, Krynetski EY, Krynetskaia NF, Grieger D, Mukatira ST, Murti KG, Slaughter CA, Park HW, Evans WE: A novel CRM1-mediated nuclear export signal governs nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase following genotoxic stress. J.Biol.Chem. 2004, 279:5984-5992.

Higuchi H, Bronner CE, Park HW, Endow SA: Rapid double 8-nm steps by a kinesin mutant. EMBO J. 2004, 23:2993-2999.

Ivey RA, Zhang YM, Virga KG, Hevener K, Lee RE, Rock CO, Jackowski S, Park HW: The structure of the pantothenate kinase.ADP.pantothenate ternary complex reveals the relationship between the binding sites for substrate, allosteric regulator, and antimetabolites. J.Biol.Chem. 2004, 279:35622-35629.

Kumaraswami M, Howe MM, Park HW: Crystal structure of the Mor protein of bacteriophage Mu, a member of the Mor/C family of transcription activators. J.Biol.Chem. 2004, 279:16581-16590.

Rock CO, Park HW, Jackowski S: Role of feedback regulation of pantothenate kinase (CoaA) in control of coenzyme A levels in Escherichia coli. J.Bacteriol. 2003, 185:3410-3415.

Yun M, Bronner CE, Park CG, Cha SS, Park HW, Endow SA: Rotation of the stalk/neck and one head in a new crystal structure of the kinesin motor protein, Ncd. EMBO J. 2003, 22:5382-5389.

Yun M, Keshvara L, Park CG, Zhang YM, Dickerson JB, Zheng J, Rock CO, Curran T, Park HW: Crystal structures of the Dab homology domains of mouse disabled 1 and 2. J.Biol.Chem. 2003, 278:36572-36581.

Kwak BY, Zhang YM, Yun M, Heath RJ, Rock CO, Jackowski S, Park HW: Structure and mechanism of CTP:phosphocholine cytidylyltransferase (LicC) from Streptococcus pneumoniae. J.Biol.Chem. 2002, 277:4343-4350.

Rock CO, Heath RJ, Park HW, Jackowski S: The licC gene of Streptococcus pneumoniae encodes a CTP:phosphocholine cytidylyltransferase. J.Bacteriol. 2001, 183:4927-4931.

Yun M, Zhang X, Park CG, Park HW, Endow SA: A structural pathway for activation of the kinesin motor ATPase. EMBO J. 2001, 20:2611-2618.

Rodriguez AC, Park HW, Mao C, Beese LS: Crystal structure of a pol alpha family DNA polymerase from the hyperthermophilic archaeon Thermococcus sp. 9 degrees N-7. J.Mol.Biol. 2000, 299:447-462.

Yun M, Park CG, Kim JY, Rock CO, Jackowski S, Park HW: Structural basis for the feedback regulation of Escherichia coli pantothenate kinase by coenzyme A. J.Biol.Chem. 2000, 275:28093-28099.

Yun M, Park CG, Kim JY, Park HW: Structural analysis of glyceraldehyde 3-phosphate dehydrogenase from Escherichia coli: direct evidence of substrate binding and cofactor-induced conformational changes. Biochemistry 2000, 39:10702-10710.

Park HW, Beese LS: Protein farnesyltransferase. Curr.Opin.Struct.Biol. 1997, 7: 873-880.

Park HW, Boduluri SR, Moomaw JF, Casey PJ, Beese LS: Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution. Science 1997, 275:1800-1804.

Park HW, Kim ST, Sancar A, Deisenhofer J: Crystal structure of DNA photolyase from Escherichia coli. Science 1995, 268:1866-1872.

Park HW, Sancar A, Deisenhofer J: Crystallization and preliminary crystallographic analysis of Escherichia coli DNA photolyase. J.Mol.Biol. 1993, 231:1122-1125.

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