The Crystal Structure of ATP-bound Phosphofructokinase from Trypanosoma brucei Reveals Conformational Transitions Different from those of Other Phosphofructokinases
The Crystal Structure of ATP-bound Phosphofructokinase from Trypanosoma brucei Reveals Conformational Transitions Different from those of Other Phosphofructokinases
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DOI：
10.1016/j.jmb.2008.11.047
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发表时间：
2009-02-06
影响因子：
5.6
通讯作者：
Walkinshaw, Malcolm D.
中科院分区：
文献类型：
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作者：
McNae, Iain W.;Martinez-Oyanedel, Jose;Walkinshaw, Malcolm D.
来自布氏锥虫的四聚体磷酸果糖激酶（PFK）的ATP结合形式的晶体结构使得能够与相同酶的脱辅基酶形式的结构进行详细的比较，以及与细菌ATP依赖性和PPi依赖性PFK的结构进行详细的比较。布氏锥虫PFK的活性位点（严格依赖ATP，但通过序列相似性属于PPi依赖家族）是两种PFK的嵌合体。特别地，布氏锥虫PFK的活性位点具有两种类型PFK的特征性氨基酸残基和结构特征。观察到ATP结合后的构象变化，包括活性位点的开放以容纳两种底物MgATP和果糖6-磷酸，以及C-末端螺旋的戏剧性排序，其作用类似于达到臂以将四聚体保持在一起。这些构象转变与其他ATP依赖性PFK的构象转变有着根本的不同。与细菌和哺乳动物PFKs相比，布氏锥虫PFK在结构和机制上的实质性差异为发现用于治疗由锥虫科的原生寄生虫引起的疾病的物种特异性药物提供了乐观。皇冠版权所有（C）2008由爱思唯尔有限公司出版。保留所有权利。
The crystal structure of the ATP-bound form of the tetrameric phosphofructokinase (PFK) from Trypanosoma brucei enables detailed comparisons to be made with the structures of the apoenzyme form of the same enzyme, as welt as with those of bacterial ATP-dependent and PPi-dependent PFKs. The active site of T brucei PFK (which is strictly ATP-dependent but belongs to the PPi-dependent family by sequence similarities) is a chimera of the two types of PFK. In particular, the active site of T brucei PFK possesses amino acid residues and structural features characteristic of both types of PFK. Conformational changes upon ATP binding are observed that include the opening of the active site to accommodate the two substrates, MgATP and fructose 6-phosphate, and a dramatic ordering of the C-terminal helices, which act like reaching arms to hold the tetramer together. These conformational transitions are fundamentally different from those of other ATP-dependent PFKs. The substantial differences in structure and mechanism of T brucei PFK compared with bacterial and mammalian PFKs give optimism for the discovery of species-specific drugs for the treatment of diseases caused by protist parasites of the trypanosomatid family. Crown Copyright (C) 2008 Published by Elsevier Ltd. All rights reserved.