Funded Studies
Objective/Rationale:
Mutations in the gene encoding Leucine Rich Repeat Kinase 2 (LRRK2) are found in a substantial number of patients with familial or sporadic forms of Parkinson’s disease, and it has been suggested that LRRK2 inhibitors may be useful therapeutics to prevent or treat the symptoms of Parkinson’s disease. In this project we will obtain the first X-ray crystal structure of LRRK2 which will help identify and develop LRRK2 inhibitors.
Project Description:
We will create a synthetic gene that encodes the LRRK2 kinase and use this to express the protein in insect cells. We will purify the protein to extremely high levels, and use this protein to generate protein crystals of LRRK2. Once protein crystals have been obtained, we will use X-ray diffraction methods to visualize the individual atoms of the LRRK2 kinase. This allows us to generate a detailed picture of exactly what the kinase looks like and therefore how chemicals could be developed to inhibit LRRK2.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Structure based drug design (SBDD) is a powerful approach that has been successfully used to identify and develop kinase inhibitors which have been proven to be very beneficial drugs (e.g. Gleevec). An X-ray crystal structure of LRRK2 will allow a variety of SBDD methods to be applied to Parkinson’s disease. The structure will therefore increase the likelihood of developing a useful drug for the treatment of Parkinson’s disease.
Anticipated Outcome:
Small molecule inhibitors of LRRK2 have the potential to prevent the onset of Parkinson’s disease. The identification and development of these small molecules is a difficult and time consuming process and an X-ray crystal structure of LRRK2 will greatly facilitate the identification and development of these small molecules.