Pompe disease, a rare lysosomal storage disease caused by deficiency of the lysosomal acid α-glucosidase (GAA), is characterized by glycogen accumulation, triggering severe secondary cellular damage and resulting in progressive motor handicap and premature death. Numerous disease-causing mutations in the gaa gene have been reported, but the structural effects of the pathological variants were unknown. Here we present the high-resolution crystal structures of recombinant human GAA (rhGAA), the standard care of Pompe disease. These structures portray the unbound form of rhGAA and complexes thereof with active site-directed inhibitors, providing insight into substrate recognition and the molecular framework for the rationalization of the deleterious effects of disease-causing mutations. Furthermore, we report the structure of rhGAA in complex with the allosteric pharmacological chaperone N-acetylcysteine, which reveals the stabilizing function of this chaperone at the structural level.

中文翻译：

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人溶酶体酸α-葡萄糖苷酶的结构-庞贝病治疗指南。

庞贝病是一种因溶酶体酸α-葡萄糖苷酶（GAA）缺乏而引起的罕见的溶酶体贮积病，其特征是糖原积累，触发严重的继发性细胞损伤并导致进行性运动障碍和过早死亡。已经报道了gaa基因中许多致病突变，但尚不清楚病理变异的结构作用。在这里，我们介绍了重组人GAA（rhGAA）（庞贝病的标准护理）的高分辨率晶体结构。这些结构描绘了rhGAA的未结合形式及其与活性定点抑制剂的复合物，提供了对底物识别和合理化致病突变有害影响的分子框架的见识。此外，