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Structural Studies on LRRK2 Kinase Using X-Ray Crystallography

This grant builds upon the research from a prior grant: Structure Window into LRRK2: Kinase or Pseudokinase?

Promising Outcomes of Original Grant:
Our initial grant, led by Dr. Susan Taylor, focused on the structural organization of a protein called LRRK2, an enzyme that transfers small chemical groups called phosphates to other proteins. These phosphates are signals that regulate cellular functions. In Parkinson's disease (PD), LRRK2 is altered by an exchange of some of its basic building blocks called amino acids. These mutations make LRRK2 more efficient in transferring phosphates and results in the development of PD. Understanding the structure of LRRK2 will tell us how LRRK2 is activated in PD. This study will use electron microscopy (high magnification technique) to study this protein. This technique allows us to establish a medium resolution structural model showing how domains (specific sites on proteins) of LRRK2 interact.


Objectives for Supplemental Investigation:
With this supplemental investigation, we would like to improve the protein crystals of LRRK2 that we recently obtained but are not yet suitable for determining of a high-quality structure. Protein crystals are very difficult to obtain and require large amounts of highly purified and stable protein. Thus, obtaining initial crystals was a major step forward in the determination of LRRK2 structure. Once we improve the current crystals, will use X-rays to determine the structure of LRRK2. This will enable us to determine how drug molecules bind LRRK2 and how they can be improved. Crystal optimization procedures include increasing the stability of the protein using chemical inhibitors and by natural or artificial proteins that interact with the surface of LRRK2, alteration of the protein by exchanging one or more of its basic building blocks and crystallization in a microgravity environments in the NASA space station.

Importance of This Research for the Development of a New PD Therapy:
A structural model of the protein LRRK2 will explain how this protein is regulated and how mutations causing PD will work. It will also significantly help us design new specific inhibitors for the development of new drugs that bind to LRRK2. We also hope that the structural model of LRRK2 will reveal additional binding pockets that can be explored for inhibitor development in addition to the currently targeted binding site in the kinase domain of this protein.


Researchers

  • Stefan Knapp, PhD

    Frankfurt am Main Germany


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