Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Univ, AFMB, 163 Avenue de Luminy, 13288, Marseille, France.
Institute of Biosciences and Bioresources, National Research Council of Italy, Via P. Castellino 111, 80131, Naples, Italy.
Nat Commun. 2017 Oct 24;8(1):1111. doi: 10.1038/s41467-017-01263-3.
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.
庞贝病是一种罕见的溶酶体贮积病，由溶酶体酸性α-葡萄糖苷酶（GAA）缺乏引起，其特征是糖原积累，引发严重的继发细胞损伤，导致进行性运动障碍和过早死亡。已报道了 gaa 基因的许多致病突变，但病理变异的结构影响尚不清楚。在这里，我们展示了重组人 GAA（rhGAA）的高分辨率晶体结构，这是庞贝病的标准治疗方法。这些结构描绘了未结合形式的 rhGAA 及其与活性位点定向抑制剂的复合物，为底物识别提供了深入了解，并为合理化致病突变的有害影响提供了分子框架。此外，我们还报告了 rhGAA 与别构药理伴侣 N-乙酰半胱氨酸的复合物结构，该结构揭示了该伴侣在结构水平上的稳定功能。
