High resolution crystal structure of human Rab9 GTPase - A novel antiviral drug target
High resolution crystal structure of human Rab9 GTPase - A novel antiviral drug target
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DOI：
10.1074/jbc.m407114200
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发表时间：
2004-09-17
影响因子：
4.8
通讯作者：
Meehan, EJ
中科院分区：
文献类型：
--
作者：
Chen, LQ;DiGiammarino, E;Meehan, EJ
Rab GTP酶和它们的效应子通过将供体囊泡束缚到它们各自的靶膜上来促进囊泡转运。Rab 9介导晚期内体到高尔基体的转运，最近发现Rab 9是人类免疫缺陷病毒-1、埃博拉病毒、马尔堡病毒和麻疹病毒复制的关键细胞组分，这表明Rab 9可能是开发广谱抗病毒药物的新靶点。作为我们基于结构的药物设计计划的一部分，我们已经确定了C-末端截短的人Rab 9（残基1-177）的晶体结构，分辨率为1.25埃。整体结构显示出特征性核苷酸结合折叠，其由五个α-螺旋包围的六链β-折叠组成，活性位点中具有紧密结合的GDP分子。Rab 9与其他Rab蛋白基于结构的序列比对表明，其活性位点由Rab GTPase家族中高度保守的残基组成，这意味着共同的催化机制。然而，Rab 9包含七个区域，这些区域在构象上与其他Rab蛋白质显著不同。这些区域中的一些与推定的效应子结合位点以及通过结构/序列比对鉴定的开关I和开关II区域一致。近原子分辨率的Rab 9结构为基于结构的抗病毒药物设计提供了一个很好的模型。
Rab GTPases and their effectors facilitate vesicular transport by tethering donor vesicles to their respective target membranes. Rab9 mediates late endosome to trans-Golgi transport and has recently been found to be a key cellular component for human immunodeficiency virus-1, Ebola, Marburg, and measles virus replication, suggesting that it may be a novel target in the development of broad spectrum antiviral drugs. As part of our structure-based drug design program, we have determined the crystal structure of a C-terminally truncated human Rab9 (residues 1-177) to 1.25-Angstrom resolution. The overall structure shows a characteristic nucleotide binding fold consisting of a six-stranded beta-sheet surrounded by five alpha-helices with a tightly bound GDP molecule in the active site. Structure-based sequence alignment of Rab9 with other Rab proteins reveals that its active site consists of residues highly conserved in the Rab GTPase family, implying a common catalytic mechanism. However, Rab9 contains seven regions that are significantly different in conformation from other Rab proteins. Some of those regions coincide with putative effector-binding sites and switch I and switch II regions identified by structure/sequence alignments. The Rab9 structure at near atomic resolution provides an excellent model for structure-based antiviral drug design.