Browsing by Subject "Roc"

Now showing 1 - 3 of 3
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    Roc, the G-domain of the Parkinson's disease-associated protein LRRK2
    (Elsevier, 2022-12) Park, Yangshin; Liao, Jingling; Hoang, Quyen Q.; Biochemistry and Molecular Biology, School of Medicine
    Mutation in LRRK2 (Leucine-rich repeat kinase 2) is a common cause of Parkinson’s disease. Aberrant LRRK2 kinase activity is associated with disease pathogenesis, and thus it is an attractive drug target for combating PD. Intense efforts in the past nearly two decades have focused on developing small-molecule inhibitors of the kinase domain of LRRK2, which have identified potent kinase inhibitors. However, most LRRK2 kinase inhibitors have shown adverse effects; therefore, alternative mechanism-based strategies are desperately needed. In this review, we will discuss the new insights gleaned from recent cryo-EM structures of LRRK2 towards understanding the mechanisms of actions of LRRK2 and explore the potential new therapeutic avenues.
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    Roc, the G-domain of the Parkinson’s disease-associated protein LRRK2
    (Elsevier, 2022) Park, Yangshin; Liao, Jingling; Hoang, Quyen Q.; Biochemistry and Molecular Biology, School of Medicine
    Mutation in LRRK2 (Leucine-rich repeat kinase 2) is a common cause of Parkinson’s disease. Aberrant LRRK2 kinase activity is associated with disease pathogenesis, and thus it is an attractive drug target for combating PD. Intense efforts in the past nearly two decades have focused on developing small-molecule inhibitors of the kinase domain of LRRK2, which have identified potent kinase inhibitors. However, most LRRK2 kinase inhibitors have shown adverse effects; therefore, alternative mechanism-based strategies are desperately needed. In this review, we will discuss the new insights gleaned from recent cryo-EM structures of LRRK2 towards understanding the mechanisms of actions of LRRK2 and explore the potential new therapeutic avenues.
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    Roco Proteins and the Parkinson's Disease-Associated LRRK2
    (MDPI, 2018-12-17) Liao, Jingling; Hoang, Quyen Q.; Biochemistry and Molecular Biology, School of Medicine
    Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes.