首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pharmacological chaperones for human α-N-acetylgalactosaminidase
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Pharmacological chaperones for human α-N-acetylgalactosaminidase

机译:人α-N-乙酰半乳糖苷酶的药理伴侣

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摘要

Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-N-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human a-NAGal both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human a-NAGal in Schindler/ Kanzaki disease. The 1.4- and 1.5-A crystal structures of human a-NAGal complexes reveal the different binding modes of iminosu-gars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases.
机译:辛德勒/坎扎基病是一种遗传性代谢疾病,目前尚无治疗方法。这种神经系统疾病是由溶酶体α-N-乙酰半乳糖苷酶(α-NAGAL)缺陷引起的。在这份报告中,我们显示了亚氨基糖DGJNAc可以在体外和体内抑制,稳定和伴侣人a-NAGal的证据。我们证明,相关的亚氨基糖DGJ(目前正在另一种代谢性疾病Fabry疾病的III期临床试验中)也可以在Schindler / Kanzaki疾病中伴侣人a-NAGal。人α-NAGal复合物的1.4-和1.5-A晶体结构与糖苷相比揭示了亚氨基糖-糖的不同结合方式。我们展示了两个官能团之间的差异如何导致> 9 kcal / mol的额外结合能,并解释了导致药理学分子伴侣的意外高亲和力的分子相互作用。这些结果为Schindler / Kanzaki疾病的治疗开辟了两条途径,并阐明了整个溶酶体贮积病家族中药理伴侣的原子基础。

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