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首页> 外文期刊>Biochemistry >The Structure of the Candida albicans Essl Prolyl Isomerase Reveals a Weil-Ordered Linker that Restricts Domain Mobility
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The Structure of the Candida albicans Essl Prolyl Isomerase Reveals a Weil-Ordered Linker that Restricts Domain Mobility

机译:白色念珠菌Essl脯氨酰异构酶的结构揭示了限制域迁移的威尔有序接头。

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摘要

Ess1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that binds to the carboxy-terminal domain (CTD) of RNA polymerase II.Essl is thought to function by inducing conformational changes in the CTD that control the assembly of cofactor complexes on the transcription unit.Essl (also called Pin1) is highly conserved throughout the eukaryotic kingdom and is required for growth in some species,including the human fungal pathogen Candida albicans.Here we report the crystal structure of the C.albicans Essl protein,determined at 1.6 A resolution.The structure reveals two domains,the WW and the isomerase domain,that have conformations essentially identical to those of human Pinl.However,the linker region that joins the two domains is quite different.In human Pinl,this linker is short and flexible,and part of it is unstructured.In contrast,the fungal Essl linker is highly ordered and contains a long alpha-helix.This structure results in a rigid juxtaposition of the WW and isomerase domains,in an orientation that is distinct from that observed in Pinl,and that eliminates a hydrophobic pocket between the domains that was implicated as the main substrate recognition site.These differences suggest distinct modes of interaction with long substrate molecules,such as the CTD of RNA polymerase II.We also show that C.albicans essl~- mutants are attenuated for in vivo survival in mice.Together,these results suggest that CaEssl might constitute a useful antifungal drug target,and that structural differences between the fungal and human enzymes could be exploited for drug design.
机译:Ess1是一种肽基脯氨酰顺/反异构酶(PPIase),可与RNA聚合酶II的羧基末端结构域(CTD)结合.Ess1被认为可通过诱导CTD构象变化来发挥作用,从而控制辅酶复合物在细胞表面的组装。转录单位.Essl(也称为Pin1)在整个真核生物王国中都是高度保守的,并且是某些物种(包括人类真菌病原体白色念珠菌)生长所必需的。在这里,我们报告了白色念珠菌Essl蛋白的晶体结构,确定为1.6一种分辨率。该结构揭示了两个结构域,即WW和异构酶结构域,其构象与人Pinl的构象基本相同。但是,连接这两个域的接头区域却大不相同。在人Pinl中,该接头短且相比之下,真菌Essl连接子是高度有序的,并含有长的α-螺旋。这种结构导致WW和异构酶结构域在一个n方向不同于Pinl中观察到的方向,并消除了涉及主要底物识别位点的结构域之间的疏水性口袋。这些差异表明与长底物分子的相互作用方式不同,例如RNA聚合酶II的CTD我们还显示白色念珠菌的essl〜-突变体在小鼠体内的存活力减弱。这些结果共同表明,CaEssl可能构成有用的抗真菌药物靶标,并且可以利用真菌和人类酶之间的结构差异药物设计。

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