Structure and Function of ICMT Methyltransferase

描述(由申请人提供)：CAAX基序的翻译后修饰提供了一种调节细胞信号蛋白的方法，包括RAS。CAAX基序的加工涉及三种顺序作用的酶：蛋白戊烯基转移酶、prenyI-CAAX酶和异丙基半胱氨酸羧甲基转移酶(ICMT)。前烯基转移酶的药理抑制已显示出作为一种抗癌治疗的有效性。ICMT的生化抑制使其对RAS依赖的致癌转化产生抵抗。ICMT的药物抑制剂缺乏，但将为治疗开发提供一条途径。本研究建议研究ICMT的结构和功能，以更好地了解其酶机制、结构，并制定抑制策略。这一过程将包括ICMT的纯化和溶解，并伴随着酶分析以确保ICMT的活性和确定ICMT的作用机制。此外，还将确定人ICMT的结构，以用于辅助酶抑制剂的设计和进一步了解ICMT蛋白质甲基化的分子机制。这些数据将详细描述ICMT的生化和结构特性，重点是抑制作用。

DESCRIPTION (provided by applicant): Post-translational modification of CaaX motifs provides a means to regulate cell signaling proteins, including Ras. The processing of CaaX motifs involves three sequentially acting enzymes: protein prenyltransferases, prenyI-CaaX proteases, and isoprenylcysteine carboxyl methyltransferase (ICMT). Pharmacologic inhibition of prenyltransferase has shown utility as an anti-cancer therapy. Biochemical inhibition of ICMT confers resistance to Ras dependent oncogenic transformation. Pharmacologic inhibitors of ICMT are lacking but would provide an avenue for therapeutic development. This study proposes to study the structure and function of ICMT to better understand its enzymatic mechanism, structure, and to develop inhibition strategies. This process will include purification and solublization of ICMT, accompanied by enzymatic analysis to insure activity and determine the mechanism of action for ICMT. Additionally the structure of human ICMT will be determined for use in aiding enzyme inhibitor design and further understanding of the molecular mechanism of ICMT methylation of proteins. This data will provide a detailed description of the biochemical and structural properties of ICMT, with a focus on inhibition.