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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Crystallographic studies of two variants of Pseudomonas aeruginosa IMPDH with impaired allosteric regulation
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Crystallographic studies of two variants of Pseudomonas aeruginosa IMPDH with impaired allosteric regulation

机译：晶体研究的两个变量铜绿假单胞菌IMPDH受损变构调节

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摘要

Inosine-5'-monophosphate dehydrogenases (IMPDHs), which are the rate-limiting enzymes in guanosine-nucleotide biosynthesis, are important therapeutic targets. Despite in-depth functional and structural characterizations of various IMPDHs, the role of the Bateman domain containing two CBS motifs remains controversial. Their involvement in the allosteric regulation of Pseudomonas aeruginosa IMPDH by Mg-ATP has recently been reported. To better understand the function of IMPDH and the importance of the CBS motifs, the structure of a variant devoid of these modules (Delta CBS) was solved at high resolution in the apo form and in complex with IMP. In addition, a single amino-acid substitution variant, D199N, was also structurally characterized: the mutation corresponds to the autosomal dominant mutant D226N of human IMPDH1, which is responsible for the onset of the retinopathy adRP10. These new structures shed light onto the possible mechanism of regulation of the IMPDH enzymatic activity. In particular, three conserved loops seem to be key players in this regulation as they connect the tetramer-tetramer interface with the active site and show significant modification upon substrate binding.
机译：Inosine-5”一磷酸脱氢酶(IMPDHs),的病原反应酶guanosine-nucleotide生物合成,是很重要的治疗的目标。和结构不同的性格特征IMPDHs,贝特曼的作用域包含两个CBS图案仍然是有争议的。参与的变构调节铜绿假单胞菌IMPDH Mg-ATP已经最近报道。函数IMPDH和哥伦比亚广播公司(CBS)的重要性没有主题,结构的变体这些模块(δCBS)是解决在高决议在apo形式和复杂小鬼。此外,一个单一的氨基酸D199N替换变体,也是结构特点:突变对应的常染色体显性突变人类IMPDH1 D226N,负责视网膜病变的发病adRP10。结构与可能机制监管的IMPDH酶活性。特别地,三个守恒的循环似乎是关键玩家在本条例连接tetramer-tetramer界面活性部位,对底物显示重要的修改绑定。

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