STRUCTURE DETERMINATION OF MITONEET, A POTENTIAL TARGET FOR DIABETES INHIBITION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在美国肥胖率上升的同时，与肥胖相关的疾病急剧增加，最明显的是2型糖尿病。据预测，这种疾病在未来几十年内将达到流行的程度。治疗II型糖尿病的首选药物是吡格列酮，这是一种噻唑烷二酮(TZD)衍生物，最初被认为通过激活核转录因子PPAR发挥作用。最近，利用从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.和Jennings，P.A.proc]收集的数据，确定了一种新的蛋白质靶标mitoNEET的结构分辨率为1.5？娜塔莉。阿卡德。SCI。美国第104,14342(2007年)]。MitoNEET是基于结构的药物设计的一个特别有趣的目标，因为它结合了胰岛素增敏药物，并且它拥有一种新的分子结构，其中包括一个异常不稳定的铁-硫簇。今年继续对mitoNEET进行结构研究，目的是研究与药物吡格列酮结合的结构，并观察在较低pH下的结构变化。将采取几种方法来解决将吡格列酮掺入晶体中的挑战。

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.