X-ray structure of human acid-β-glucosidase, the defective enzyme in Gaucher disease
X-ray structure of human acid-β-glucosidase, the defective enzyme in Gaucher disease
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DOI：
10.1038/sj.embor.embor873
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发表时间：
2003-07-01
期刊：
影响因子：
7.7
通讯作者：
Sussman, JL
中科院分区：
文献类型：
--
作者：
Dvir, H;Harel, M;Sussman, JL
戈谢病是最常见的溶酶体贮积病，是由编码酸性-β-葡萄糖苷酶 (GlcCerase) 的基因突变引起的。 1 型的特点是肝脾肿大，2 型和 3 型的特点是早期或慢性发作严重的神经系统症状。尽管常见突变 N370S 和 L444P 的纯合性分别与非神经病性和神经病性疾病相关，但类似 200 个 GlcCerase 突变与疾病严重程度之间不存在明确的相关性。我们报告了 GlcCerase 分辨率为 2.0 埃的 X 射线结构。催化结构域由 (beta/alpha)(8) TIM 桶组成，正如葡萄糖苷酶水解酶 A 家族成员所预期的那样。催化残基E235和E340之间的距离与催化保留机制一致。 N370 位于最长的 α 螺旋（螺旋 7）上，该螺旋还有其他几个指向 TIM 桶的残基突变。螺旋 7 位于 TIM 桶和 L444 所在的独立免疫球蛋白样结构域之间的界面，表明该非催化结构域具有重要的调节或结构作用。该结构为设计改进的 GlcCerase 用于酶替代疗法以及设计旨在恢复有缺陷的 GlcCerase 活性的基于结构的药物提供了可能性。
Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. No clear correlation exists between the similar to 200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with nonneuronopathic and neuronopathic disease, respectively. We report the X-ray structure of GlcCerase at 2.0 Angstrom resolution. The catalytic domain consists of a (beta/alpha)(8) TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest alpha-helix (helix 7), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin- like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase.