Design and Identification of a LRRK2 Kinase Structural Surrogate

Study Rationale:

Due to the importance of the LRRK2 protein in Parkinson's disease (PD), many academic and industrial laboratories have attempted to solve the three-dimensional structure of the kinase domain of LRRK2; however, no such structure has yet been described. Several classes of LRRK2 inhibitors have been disclosed but their optimization is hampered by a lack of experimental LRRK2-compound structures. A LRRK2-like structural surrogate can accelerate these classes of inhibitors.

Hypothesis:

The objective of this project is to develop a LRRK2 structural reagent to shed light on LRRK2 compounds which bind to the adenosine triphosphate (high-energy molecule; ATP) binding site.

Study Design:

Kinase inhibitor properties are dictated primarily by residues surrounding the ATP binding site; however, crystallization properties are dictated by the protein residues at the protein surface. We aim to build a LRRK2-like inhibitor profile onto a kinase scaffold (support structure) known to crystallize.

Impact on Diagnosis/Treatment of Parkinson's disease:

A structural surrogate for LRRK2 kinase will accelerate discovery, characterization and optimization of novel inhibitors for PD.

Next Steps for Development:

The development of LRRK2 therapeutic molecules will be accelerated by creation of a LRRK2-like structural surrogate.