STRUCTURAL DETERMINANTS FOR THE ALLOSTERIC REGULATION OF MAMMALIAN PEPCK

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 磷酸烯醇式丙酮酸羧激酶（PEPCK）是植物异生过程中的关键酶。与其他关键代谢酶不同，PEPCK是一种单体酶，没有已知的生理功能调节剂。我们的结构研究表明，与目前的理解相反，PEPCK包含一个隐藏的变构stite。配体在该位点的结合诱导构象变化，排除核苷酸结合。为了支持我们的假设和我们的动力学数据，我们需要高分辨率的数据与一系列的抑制剂结合到这个网站的PEPCK复合物。这些数据将使我们能够在PEPCK的这个以前未被重视的调节位点上开发分子识别模型，并确定这种调节是否与体内PEPCK的代谢调节有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in gluconeogenesis. Unlike other key metabolic enzymes, PEPCK is a monomeric enzyme with no known physiological regulators of function. Our structural studies demonstrate that in contrast to current understanding, PEPCK contains a hidden allosteric stite. Ligand binding at this site induces a conformational change, precluding nucleotide binding. In order to support our hypothesis and our kinetic data we require high-resolution data on complexes of PEPCK with a series of inhibitors that bind to this site. This data will allow us to develop a model of molecular recognition at this previously unappreciated regulatory site on PEPCK and determine if this regulation has any relevance to metabolic regulation of PEPCK in vivo.