PMC

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).

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.

(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.

(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.