Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, United Kingdom.
Bioorg Med Chem. 2013 Aug 15;21(16):4751-4. doi: 10.1016/j.bmc.2013.05.056. Epub 2013 Jun 13.
Fucosidases, enzymes that cleave fucose from the non-reducing end of a glycan, represent promising medicinal targets reflecting their roles in cancer metastasis, inflammation, host-parasite interactions and the lysosomal storage disorder fucosidosis. The X-ray crystal structures of Bacteroides thetaiotaomicron GH29 α-l-fucosidase (BtFuc2970) in a new crystal form (at a resolution of 1.59Å) and liganded with a 5-membered iminocyclitol inhibitor (1.73Å) are reported herein. The 5-membered iminocyclitol binds in a (3)E conformation, mimicking the proposed (3)H4 half chair transition-state of the enzyme catalysed reaction, and its Ki for BtFuc2970 was determined as 2μM. Structural analysis of fucosidase inhibition through 5-membered iminocyclitols will aid in the rational design of more potent fucosidase inhibitors for treatment of a range of medical conditions.
岩藻糖苷酶能够从聚糖的非还原端切割岩藻糖，是癌症转移、炎症、宿主-寄生虫相互作用以及溶酶体贮积病岩藻糖贮积症等过程中的重要药物靶点。本文报道了产黏液拟杆菌 GH29 α-L-岩藻糖苷酶（BtFuc2970）在一种新晶体形式（分辨率为 1.59Å）和与五元亚氨基环糖醇配体（分辨率为 1.73Å）结合的 X 射线晶体结构。五元亚氨基环糖醇以（3）E 构象结合，模拟酶催化反应中所提出的（3）H4 半椅过渡态，其对 BtFuc2970 的 Ki 值为 2μM。通过五元亚氨基环糖醇对岩藻糖苷酶抑制作用的结构分析，将有助于合理设计更有效的岩藻糖苷酶抑制剂，用于治疗一系列医学病症。
