Roc, the G-domain of the Parkinson's disease-associated protein LRRK2

Trends Biochem Sci. 2022 Dec;47(12):1038-1047. doi: 10.1016/j.tibs.2022.06.009. Epub 2022 Jul 12.

Abstract

Mutation in leucine-rich repeat (LRR) kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD). 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 the development of small-molecule inhibitors of the kinase domain of LRRK2 and 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 discuss the new insights gleaned from recent cryoelectron microscope (cryo-EM) structures of LRRK2 towards understanding the mechanisms of actions of LRRK2 and explore the potential new therapeutic avenues.

Keywords: COR; GTPase; Roc; allosteric regulation; kinase; therapeutics.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / chemistry
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Mutation
  • Parkinson Disease* / drug therapy
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Protein Serine-Threonine Kinases

Substances

  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • LRRK2 protein, human