title: Current understanding of LRRK2 in Parkinson's disease: biochemical and structural features and inhibitor design.
abstract: Since leucine-rich repeat kinase 2 (LRRK2) was linked to Parkinson's disease in 2004, kinase activity of LRRK2 has been believed to play a critical role in the pathogenesis of Parkinson's disease. As a result, identification of LRRK2 inhibitors has been a focus for drug discovery. However, most LRRK2 mutations do not simply increase kinase activity. In this review we summarize the potential mechanisms that regulate the kinase activity of LRRK2. We outline some currently available kinase inhibitors, including the identification of a DFG-out (type-II) inhibitor. Finally, we discuss the relationship of LRRK2 with tau and α-synuclein. The fact that all three proteins are autophapgy-related provides a future strategy for the identification of LRRK2 physiological substrate(s).
authors.affiliation: Brigham & Women's Hospital, 65 Landsdowne Street, Fourth Floor, Cambridge, MA 02139, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Ray
authors.forename: Min
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases