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Elucidation of the steric bases of anticancer activities of interferons through a combined approach by X-ray crystal structure analyzes and protein engineering.

通过 X 射线晶体结构分析和蛋白质工程相结合的方法阐明干扰素抗癌活性的空间基础。

基本信息

批准号：
04404088
负责人：
MITSUI Yukio
金额：
$ 14.08万
依托单位：
Nagaoka University of Thchnology
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

1) Set-up of the X-ray diffractometer system.The "recording device for diffracted X-ray beam", whcih was purchased by the present grant, completed the set-up of the two-dimensional X-ray diffraactometer using Imaging Plates.2) Set-up of the computer graphics system.The "CPU-upgrading system" purchased by the present grant, was succesfully incorporated into the existing system extensively upgrading its performance.3) Refinement of the crystal structure of murine interferon-betaUsing the systems 1) and 2) above, the structure has been refined at 2.15 A resolution to an R-factor of 19.1%. Extensive modification was found necessary for the A-Helix portion (EMBO Journal 4,3193-3201 (1993) ; also submitted to J.Mol.Biol.)4) Prediction of the three-dimensional structures for various Type I interferons.Structure prediction was done for the following four interferons : human-alphaD,human-beta, bovine & ovine tau's. A huge data set of the structure-activity relationship studiesdirected for Type I interferons were compiled and systematically evaluated based on the established three-dimensional structure(Pharmacology & Therapeutics, 58,93-132 (1993)).5) Yet another challenege for the crystallization of human interferon-alpha.13EA10 : The attempt failed as before indicating that there must be some fundamental reason for non-crystallizability. More systematic approaches making use of a dynamic light scattering device (for example) would be necessary.

1)安装X射线衍射仪系统。本基金购置的“衍射X射线束记录装置”，完成了使用成像板的二维X射线衍射仪的安装。2）安装计算机图形系统。本基金购置的“中央处理器升级系统”，成功地结合到现有系统中，广泛地提高了其性能。3）鼠干扰素-β的晶体结构的精细化使用上述系统1）和2），该结构已在2.15 A分辨率下被细化到19.1%的R因子。发现对A-受阻部分进行大量修饰是必要的（EMBO Journal 4，3193 -3201（1993）;也提交给J.Mol.Biol.）4)各种I型干扰素的三维结构预测：对以下四种干扰素进行结构预测：人-α D、人-β、牛和绵羊tau。在已建立的三维结构基础上，对I型干扰素的构效关系进行了系统的评价（Pharmacology & Therapeutics，58，93 -132（1993））。5）人干扰素-α 13 EA 10结晶的另一个优点是：这种尝试和以前一样失败了，这表明非结晶性必须有一些根本原因。利用动态光散射装置（例如）的更系统的方法将是必要的。