STRUCTURE DETERMINATION OF MITONEET, A POTENTIAL TARGET FOR DIABETES INHIBITION

抑制糖尿病的潜在靶点 MITONEET 的结构测定

• 批准号: 7954400
• 负责人: AINA COHEN
• 金额: $ 0.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954400
• 关键词: 2,4-thiazolidinedione; Address; Binding; Computer Retrieval of Information on Scientific Projects Database; Data; Diabetes Mellitus; Disease; Drug Design; Epidemic; Funding; Goals; Grant; Institution; Iron; Molecular Structure; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Obesity associated disease; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pioglitazone; Proteins; Research; Research Personnel; Resolution; Resources; Source; Structure; Sulfur; Thiazolidinediones; United States; United States National Institutes of Health; base; insulin sensitizing drugs; interest; novel; structural biology; synchrotron radiation; transcription factor

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.

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在美国，肥胖症的增加与肥胖相关疾病的急剧增加相平行，最明显的是2型糖尿病。据预测，这种疾病在今后几十年内将达到流行病的程度。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，最初认为其通过激活核转录因子PPAR发挥作用。 最近，使用从BL 9 -2收集的数据将新的蛋白质靶标mitoNEET的结构确定为1.5 μ分辨率[Paddock，M. L.，Wiley，S. E、阿克塞尔罗德，H。L.，科恩，A. E、罗伊，M.，Abresch，E. C.的方法，Capraro，D.，Murphy，A. N.，Nechushtai河，狄克逊，J.E.和Jennings，P. A. Proc. Natl. Acad. Sci. USA 104，14342（2007）]。 MitoNEET是基于结构的药物设计的一个特别有趣的靶标，因为它结合胰岛素增敏药物，并且它具有一种新的分子结构，其中包括一个异常不稳定的铁-硫簇。 今年继续进行MitoNEET的结构研究，目的是研究药物吡格列酮结合的结构，并观察在较低pH值下的结构变化。将采用几种方法来解决将吡格列酮纳入晶体的挑战。