Allosteric inhibition of protein tyrosine phosphatase 1B
Allosteric inhibition of protein tyrosine phosphatase 1B
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DOI：
10.1038/nsmb803
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发表时间：
2004-08-01
影响因子：
16.8
通讯作者：
Hansen, SK
中科院分区：
文献类型：
--
作者：
Wiesmann, C;Barr, KJ;Hansen, SK
肥胖和II型糖尿病是密切相关的代谢综合征，全世界有10亿人受到影响。尽管蛋白酪氨酸磷酸酶1B （PTP1B）已成为治疗这两种综合征的有希望的靶点，但发现在活性位点结合的药学上可接受的抑制剂仍然是一个重大挑战。在这里，我们描述了在PTP1B中发现的一个变构位点。PTP1B与变构抑制剂配合物的晶体结构揭示了一个新的位点，位于与催化位点相似的20埃处。我们表明，变构抑制剂通过阻断催化环的流动性来阻止酶活性形式的形成，从而利用酪氨酸磷酸酶使用的一般机制。值得注意的是，这些抑制剂对PTP1B表现出选择性，并增强细胞中的胰岛素信号传导。变构抑制是一种很有前途的靶向PTP1B的策略，并构成了一种可能适用于其他酪氨酸磷酸酶的机制。
Obesity and type II diabetes are closely linked metabolic syndromes that afflict > 100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located similar to 20 Angstrom from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.