Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 1996-07-12 DOI:10.1126/science.273.5272.239

Jungwon Choi, Jie Chen, Stuart L. Schreiber, Jon Clardy

引用次数: 791

Abstract

Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506-binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A crystal structure of the ternary complex of human FKBP12, rapamycin, and the FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7 angstroms revealed the two proteins bound together as a result of the ability of rapamycin to occupy two different hydrophobic binding pockets simultaneously. The structure shows extensive interactions between rapamycin and both proteins, but fewer interactions between the proteins. The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants of FRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization.

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与人类 FRAP 结合域相互作用的 FKBP12-雷帕霉素复合物的结构

雷帕霉素是一种强效免疫抑制剂，能与两种蛋白质结合：FK506 结合蛋白（FKBP12）和 FKBP-雷帕霉素相关蛋白（FRAP）。分辨率为 2.7 埃的人类 FKBP12、雷帕霉素和人类 FRAP 的 FKBP12-雷帕霉素结合（FRB）结构域三元复合物晶体结构显示，由于雷帕霉素能够同时占据两个不同的疏水结合口袋，因此这两种蛋白质结合在了一起。该结构显示雷帕霉素与两种蛋白之间存在广泛的相互作用，但蛋白之间的相互作用较少。FRAP的FRB结构域的结构澄清了在FRAP突变体及其与共济失调-特朗吉特氏症突变基因产物相关的同源蛋白家族中观察到的雷帕霉素非依赖性和依赖性效应，并说明了一种细胞渗透性小分子是如何介导蛋白质二聚化的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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