STRUCTURE-FUNCTION STUDIES ON C-TERMINAL TRUNCATIONS OF 11?-HYDROXYSTEROID

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。人类11 ?- 1型羟基类固醇脱氢酶(11？-HSD1)是内质网定位的膜蛋白，催化可的松和皮质醇的相互转化。在脂肪组织中，通过11？-HSD1活性与II型糖尿病和肥胖的发病机制有关，这使得该酶成为治疗这些疾病的潜在药物靶点。最近，我们已经解决了酶胞外部分的第一个高分辨率晶体结构。我们希望就11？-HSD1与酶寡聚和还原酶活性有关。为此，我们希望对c端进行系统截断，并利用x射线晶体学来了解控制这两个相互关联功能的结构特征。

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 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) is an ER-localized membrane protein that catalyzes the interconversion of cortisone and cortisol. In adipose tissue, excessive cortisol production through 11?-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 11?-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.