Structure of acid β-glucosidase with pharmacological chaperone provides insight into Gaucher disease
Structure of acid β-glucosidase with pharmacological chaperone provides insight into Gaucher disease
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DOI：
10.1038/nchembio850
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发表时间：
2007-02-01
影响因子：
14.8
通讯作者：
Petsko, Gregory A.
中科院分区：
文献类型：
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作者：
Lieberman, Raquel L.;Wustman, Brandon A.;Petsko, Gregory A.
戈谢病由溶酶体酶酸性β-葡糖苷酶（GCase）突变引起（1）。虽然酶替代疗法改善了一些受影响个体的健康状况，例如那些具有流行N370S突变的个体，但通过恢复内源性突变GCase的足够活性，使用药理学伴侣的口服治疗可能在更广泛的组织区室中具有治疗作用（2）。在这里，我们证明，异法戈明（IFG，1）结合到GCase活性位点，并增加GCase活性在细胞裂解物和恢复溶酶体运输细胞含有N370S突变GCase。我们还比较了IFG结合的GCase在低pH值与甘油结合的GCase在低pH值和apo-GCase在中性pH值的晶体结构。我们的数据表明，IFG诱导活性GCase，这是通过与Asn370的相互作用而得到的。稳定突变蛋白质的底物结合构象的小分子的设计可能是由蛋白质错误折叠和错误激活引起的疾病的一般治疗策略。
Gaucher disease results from mutations in the lysosomal enzyme acid beta-glucosidase ( GCase)(1). Although enzyme replacement therapy has improved the health of some affected individuals, such as those with the prevalent N370S mutation, oral treatment with pharmacological chaperones may be therapeutic in a wider range of tissue compartments by restoring sufficient activity of endogenous mutant GCase(2). Here we demonstrate that isofagomine ( IFG, 1) binds to the GCase active site, and both increases GCase activity in cell lysates and restores lysosomal trafficking in cells containing N370S mutant GCase. We also compare the crystal structures of IFG-bound GCase at low pH with those of glycerol-bound GCase at low pH and apo-GCase at neutral pH. Our data indicate that IFG induces active GCase, which is secured by interactions with Asn370. The design of small molecules that stabilize substrate-bound conformations of mutant proteins may be a general therapeutic strategy for diseases caused by protein misfolding and mistrafficking.