Biochemical & Molecular Pharmacology, Structural Biology
Pantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate (Pan) in the biosynthetic pathway of coenzyme A (CoA), a metabolic cofactor essential in multiple physiological processes including the citric acid cycle and fatty acid synthesis. Thus, PanK represents an important drug target for the design of antimicrobial agents, much needed for the treatment of multidrug-resistant bacterial strains that include E. coli, K. pneumoniae, P. aeruginosa, andS. aureus. We focus on the structural analyses of human and bacterial PanKs, which will be essential in uncovering differences in their Pan-binding sites, providing the basis for the design of compounds selective toward the PanKs of pathogenic bacteria.
The kinesin superfamily members are one of the major cytoskeletal motors responsible for trafficking proteins, synaptic vesicles, and cell surface receptors. They play fundamental roles in neuronal function, plasticity, and morphogenesis, and are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Huntington’s diseases. We are interested in the characterization of the kinesin transport system by determining the structures of the kinesins in complex with its various cargoes. These structures help elucidate the mechanism of cargo selection, the regulation of cargo loading and unloading, and the involvement of kinesin in the pathogenesis of the neurodegenerative diseases.
For more information regarding Dr. Park's research, see: Structural Genomics Consortium.
Strushkevich N, Mackenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci USA. 2011; 108(25):10139-43.
Wang H, Hota PK, Tong Y, Li B, Shen L, Nedyalkova L, Borthakur S, Kim S, Tempel W, Buck M, Park HW. Structural Basis of Rnd1 Binding to Plexin Rho GTPase Binding Domains (RBDs). J Biol Chem. 2011; 286(29):26093-106.
Tong Y, Tempel W, Wang H, Yamada K, Shen L, Senisterra GA, MacKenzie F, Chishti AH, Park HW. Phosphorylation-independent dual-site binding of the FHA domain of KIF13 mediates phosphoinositide transport via centaurin alpha1.Proc Natl Acad Sci USA. 2010; 107(47):20346-51.
Hong BS, Allali-Hassani A, Tempel W, Finerty PJ Jr, Mackenzie F, Dimov S, Vedadi M, Park HW. Crystal structures of human choline kinase isoforms in complex with hemicholinium-3: single amino acid near the active site influences inhibitor sensitivity. J Biol Chem. 2010; 285(21):16330-40.
Wiens CJ, Tong Y, Esmail MA, Oh E, Gerdes JM, Wang J, Tempel W, Rattner JB, Katsanis N, Park HW, Leroux MR. Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. J Biol Chem. 2010; 285(21):16218-30.
Strushkevich N, Usanov SA, Park HW. Structural basis of human CYP51 inhibition by antifungal azoles. J Mol Biol.2010; 397(4):1067-78.
Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections. Lepesheva GI, Park HW, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR. J Biol Chem. 2010; 285(3):1773-80.
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.