The Structural Basis for the Selectivity of Benzotriazole Inhibitors of PTP1B

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• 作者：Giovanna Scapin ; Sangita B. Patel ; Joseph W. Becker ; Qingping Wang ; Caroline Desponts ; Deena Waddleton ; Kathryn Skorey ; Wanda Cromlish ; Christopher Bayly ; Michel Therien ; Jacques Yves Gauthier ; Chun S
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：October 7, 2003
• 年：2003
• 卷：42
• 期：39
• 页码：11451 - 11459
• 全文大小：353K
• 年卷期：v.42,no.39(October 7, 2003)
• ISSN：1520-4995

文摘

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulinsignaling pathway and represents an attractive target for the design of inhibitors in the treatment of type2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors maybe obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We reporthere the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket nearthe primary binding site, the second generation compounds also reach into the secondary binding site,and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecularbasis for the selectivity has been confirmed by single point mutation at position 52, where the twophosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform forthe development of potent and selective PTP1B inhibitors.