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).

Figure 1. Position of Parkinson's disease-linked mutations of LRRK2 indicated on linear domain structure and homology models

(A) A linear representation of LRRK2 sequence and the domain organization with some of the most commonly occurring Parkinson's disease mutations annotated on these domains. The two mutations in the kinase activation loop G2019S and I2020T are indicated in italics. (B) Ribbon representation of the x-ray structure of the GTPase domain of LRRK2 (2ZEJ) showing the positions of Parkinson's disease-linked mutations. (C) Ribbon representation of the kinase domain of LRRK2 showing the positions of various Parkinson's disease-linked mutations. The mutations in the activation loop G2019S and I2020T are indicated in italics.

Figure 2. Structural details of the ATP-binding site of LRRK2

The DYG regulatory motif is shown in the `DYG-in' state. D2017 participates in a hydrogen bond with Mg²⁺ ion and ATP molecule in the binding pocket. The CPK representations of the Parkinson's disease-associated mutations G2019S (orange) and I2020T (purple) are shown on the activation loop.

Figure 3. Ribbon representation of the active and inactive forms of LRRK2

D2017 and Y2018 act as bipositional switches that exchange positions as the enzyme switches between the active and inactive form (DYG-in: green; DYG-out: red). The mutations in the activation loop G2019S and I2020T are indicated by CPK representation (G2019S: orange; I2020T: pink).

Figure 4. Homology model of LRRK2 bound to the DFG-out inhibitor sorafenib

(A) Ribbon diagram with residues that interact with sorafenib in stick repesentation is shown in this figure. Sorafenib is shown to bind in the DYG-out conformation making interactions with both the ATP-binding hinge region of the kinase as well as the DYG-out allosteric pocket. (B) A ligand interaction diagram for the model of LRRK2 bound to sorafenib is shown here. All residues with 4.0A distance are highlighted. Hydrophobic residues are shown in green, red indicates negatively charged residues, blue indicates positively charged residues. The arrows indicate hydrogen bonds.