Nature Structural & Molecular Biology11, 730 - 737 (2004)
Published online: 18 July 2004; | doi:10.1038/nsmb803
Allosteric inhibition of protein tyrosine phosphatase 1B
Christian Wiesmann1, 2, 3, Kenneth J Barr1, 3, Jenny Kung1, 3, Jiang Zhu1, Daniel A Erlanson1, Wang Shen1, Bruce J Fahr1, Min Zhong1, Lisa Taylor1, Mike Randal1, Robert S McDowell1
& Stig K Hansen1
1
Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA.
2
Present address: Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
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 20 Å 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.
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20 Å 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.
