STRUCTURE-FUNCTION STUDIES ON C-TERMINAL TRUNCATIONS OF 11BHYDROXYSTERIOD DEHYDR

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。 人11β-羟基类固醇脱氢酶1(11β-HSD1)是一种内质网定位的膜蛋白，催化皮质醇和皮质醇的相互转化。在脂肪组织中，通过11β-HSD1活性过度产生的皮质醇与II型糖尿病和肥胖症的发病机制有关，这使得这种酶成为治疗这些疾病的潜在药物靶点。最近，我们解决了该酶胞外部分的第一个高分辨率晶体结构。我们希望在酶齐聚和还原酶活性方面对11beta-HSD1进行进一步的研究。为此，我们希望对C-末端进行系统的截断，并使用X射线结晶学来了解控制这两个相互关联的功能的结构特征。

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. Human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an ER-localized membrane protein that catalyzes the interconversion of cortisone and cortisol. In adipose tissue, excessive cortisol production through 11beta-HSD1 activity has been implicated in the pathogenesis of type II diabetes and obesity, which makes this enzyme a potential drug target against these diseases. Recently we have solved the first high-resolution crystal structure of the extracellular portion of the enzyme. We wish to undertake further studies on 11beta-HSD1 with regards to enzyme oligomerization and reductase activity. To this end, we would like to carry out systematic truncations of the C-terminus and use x-ray crystallography to understand the structural features controlling these two interrelated functions.