This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our laboratory focuses on the development of ruthenium complexes as kinetically inert enzyme inhibitors. In this concept, the metal center controls the orientation of the organic ligands to achieve unique three-dimensional structures that match the enzyme active site. X-ray crystallography of target enzymes with bound organoruthenium compounds are a central part of this effort. We are now especially interested in improving the affinity and selectivity of our lead structures for GSK-3. The functilnal groups in the active side that that are responsible for the potency and selectivity of the metal complexes will be investigated by introducing mutations in the active site of GSK-3. This work will include the following aim: Obtaining co-crystal structures of native and mutant GSK-3beta with the organoruthenium inhibitors: These structures will allow us to understand the binding mode in detail and to design second generation inhibitors for GSK-3. We already obtained cocrystals with one of the first generation compounds. These crystals did not diffract at the in-house X-Ray source (R axis IV++ image plate detector mounted on a Rigaku-200HB rotating anode X-ray generator, Christianson Lab). However, we were able to collect a complete data set at CHESS F1beamline (in collaboration with Dr. David Christiansons Lab). These crystals diffracted up to 3.1 ? and the unit cell parameters were determined. The purpose of this proposal is to request beam time to collect high-resolution data sets that will be obtained from crystals with better quality.
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