Crystal Structure of β-Hexosaminidase B in Complex with Pyrimethamine, a Potential Pharmacological Chaperone
Crystal Structure of β-Hexosaminidase B in Complex with Pyrimethamine, a Potential Pharmacological Chaperone
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DOI：
10.1021/jm101443u
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发表时间：
2011-03-10
影响因子：
7.3
通讯作者：
James, Michael N. G.
中科院分区：
文献类型：
--
作者：
Bateman, Katherine S.;Cherney, Maia M.;James, Michael N. G.
己糖氨酸酶（β -hex）是一组糖基水解酶同工酶，可分解溶酶体中的中性和唾液化的鞘糖脂，从而防止其在神经元细胞中的积聚。一些β -hex突变体的折叠稳定性降低，导致成人发病形式的溶酶体贮积性疾病。然而，预防有害的糖脂积累只需要10%的野生型活性。乙胺嘧啶（PYR）是一种潜在的药理学伴侣，它的作用是充分稳定这些突变酶，使更多的-己烯进入溶酶体，在那里它可以发挥它的功能。人β -己糖氨酸酶B （HexB）与PYR复合物的x射线结构已测定为2.8埃。PYR与HexB的活性位点结合，在那里引入了几个有利的范德华键和氢键。需要对酶的结构进行微小的调整以适应配体，并讨论了PYR的抑制和稳定特性的细节。
beta-Hexosaminidases (beta-hex) are a group of glycosyl hydrolase isozymes that break down neutral and sialylated glycosphingolipids in the lysosomes, thereby preventing their buildup in neuronal cells. Some mutants of beta-hex have decreased folding stability that results in adult-onset forms of lysosomal storage diseases. However, prevention of the harmful accumulation of glycolipids only requires 10% of wild-type activity. Pyrimethamine (PYR) is a potential pharmacological chaperone that works by stabilizing these mutant enzymes sufficiently to allow more beta-hex to arrive in the lysosome, where it can carry out its function. An X-ray structure of the complex between human beta-hexosaminidase B (HexB) and PYR has been determined to 2.8 angstrom. PYR binds to the active site of HexB where several favorable van der Waals contacts and hydrogen bonds are introduced. Small adjustments of the enzyme structure are required to accommodate the ligand, and details of the inhibition and stabilization properties of PYR are discussed.