STRUCTURE DETERMINATION OF MITONEET, A POTENTIAL TARGET FOR DIABETES INHIBITION

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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. The rise in obesity in the United States parallels a dramatic increase in obesity-associated diseases, most notably type-2 diabetes. This disease is predicted to reach epidemic proportions in the next several decades. A drug of choice to treat type-II diabetes is pioglitazone, a thiazolidinedione (TZD) derivative originally thought to exert its effect through activation of the nuclear transcription factor PPAR. Recently, the structure of a novel protein target, mitoNEET, was determined to 1.5 ¿ resolution using data collected from BL9-2 [Paddock, M. L., Wiley, S. E., Axelrod, H. L., Cohen, A. E., Roy, M., Abresch, E. C., Capraro, D., Murphy, A. N., Nechushtai, R., Dixon, J. E. and Jennings, P. A. Proc. Natl. Acad. Sci. USA 104, 14342 (2007)]. MitoNEET is a particularly interesting target for structure-based drug design as it binds insulin-sensitizing drugs and it possesses a novel molecular structure which includes an unusually labile iron-sulfur cluster. Structural studies of MitoNEET were continued this year with the goals of studying the structure with the drug pioglitazone bound and to observe structural changes at lower pH. Several approaches will be pursued to address the challenge of incorporating pioglitazone into the crystals.