Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor
Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor
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DOI：
10.1074/jbc.m212491200
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发表时间：
2003-04-04
影响因子：
4.8
通讯作者：
Zhang, ZY
中科院分区：
文献类型：
--
作者：
Sun, JP;Fedorov, AA;Zhang, ZY
蛋白酪氨酸磷酸酶1B(PTP1B)是胰岛素和瘦素等多种信号通路的重要调节因子。有效和特异的PTP1B抑制剂可以作为有用的工具来阐明PTP1B的生理功能，并可能构成治疗多种人类疾病的有价值的疗法。我们已经确定了PTP1B与化合物2的络合物的晶体结构，化合物2是迄今为止报道的最有效和最选择性的PTP1B抑制剂。2.15埃分辨率的结构表明，化合物2同时结合到活性中心和由Lys-41、Arg-47和Asp-48形成的唯一的近端非催化中心。PTP1B及其定点突变体与化合物2及其几个变体相互作用的动力学分析结果进一步证实了结构数据。尽管PTP1B和化合物2之间相互作用的许多重要残基并不是PTP1B所特有的，但不同的PTP同工酶的所有接触残基的组合不同，这为有效和选择性地抑制PTP1B提供了结构基础。我们的数据进一步表明，除了先前发现的第二个芳基磷酸结合口袋外，还可以通过靶向Lys-41、Arg-47和Asp-48残基定义的区域获得有效的、高选择性的PTP1B抑制剂。
Protein-tyrosine phosphatase 1B (PTP1B) has been implicated as an important regulator in several signaling pathways including those initiated by insulin and leptin. Potent and specific PTP1B inhibitors could serve as useful tools in elucidating the physiological functions of PTP1B and may constitute valuable therapeutics in the treatment of several human diseases. We have determined the crystal structure of PTP1B in complex with compound 2, the most potent and selective PTP1B inhibitor reported to date. The structure at 2.15-Angstrom resolution reveals that compound 2 simultaneously binds to the active site and a unique proximal noncatalytic site formed by Lys-41, Arg-47, and Asp-48. The structural data are further corroborated by results from kinetic analyses of the interactions of PTP1B and its site-directed mutants with compound 2 and several of its variants. Although many of the residues important for interactions between PTP1B and compound 2 are not unique to PTP1B, the combinations of all contact residues differ between PTP isozymes, which provide a structural basis for potent and selective PTP1B inhibition. Our data further suggest that potent, yet highly selective, PTP1B inhibitory agents can be acquired by targeting the area defined by residues Lys-41, Arg-47, and Asp-48, in addition to the previously identified second aryl phosphate-binding pocket.