Browsing by Author "Oh, Misook"

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    Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein
    (PNAS, 2014-07-29) Oh, Misook; Le, Ji Hoon; Wang, Wei; Sun Lee, Hui; Sirl Lee, Woo; Burlak, Christopher; Im, Wonpil; Hoang, Quyen; Lim, Hyun-Suk; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient high-throughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complex-disease targets that are traditionally deemed "undruggable."
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    A revised 1.6 Å structure of the GTPase domain of the Parkinson’s disease-associated protein LRRK2 provides insights into mechanisms
    (Cold Spring Harbor Laboratory Press, 2019) Wu, Chun-Xiang; Liao, Jingling; Park, Yangshin; Hoang, Neo C.; Engel, Victoria A.; Wan, Li; Oh, Misook; Sanishvili, Ruslan; Takagi, Yuichiro; Johnson, Steven M.; Wang, Mu; Federici, Mark; Nichols, R. Jeremy; Beilina, Alexandra; Reed, Xylena; Cookson, Mark R.; Hoang, Quyen Q.; Biochemistry and Molecular Biology, School of Medicine
    Leucine-rich repeat kinase 2 (LRRK2) is a large 286 kDa multi-domain protein whose mutation is a common cause of Parkinson’s disease (PD). One of the common sites of familial PD-associated mutations occurs at residue Arg-1441 in the GTPase domain of LRRK2. Previously, we reported that the PD-associated mutation R1441H impairs the catalytic activity of the GTPase domain thereby traps it in a persistently "on" state. More recently, we reported that the GTPase domain of LRRK2 exists in a dynamic dimer-monomer equilibrium where GTP binding shifts it to the monomeric conformation while GDP binding shifts it back to the dimeric state. We also reported that all of the PD-associated mutations at Arg-1441, including R1441H, R1441C, and R1441G, impair the nucleotide-dependent dimer-monomer conformational dynamics of the GTPase domain. However, the mechanism of this nucleotide-dependent conformational dynamics and how it is impaired by the mutations at residue Arg-1441 remained unclear. Here, we report a 1.6 Å crystal structure of the GTPase domain of LRRK2. Our structure has revealed a dynamic switch region that can be differentially regulated by GTP and GDP binding. This nucleotide-dependent regulation is impaired when residue Arg-1441 is substituted with the PD-associated mutations due to the loss of its exquisite interactions consisting of two hydrogen bonds and a π-stacking interaction at the dimer interface.