Design and Identification of a LRRK2 Kinase Structural Surrogate
LRRK2 Research Grant, 2016
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.
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.
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.
Associate Professor at University of Groningen
Location: Groningen, Netherlands