Scapin Giovanna, Patel Sangita B, Becker Joseph W, Wang Qingping, Desponts Caroline, Waddleton Deena, Skorey Kathryn, Cromlish Wanda, Bayly Christopher, Therien Michel, Gauthier Jacques Yves, Li Chun Sing, Lau Cheuk K, Ramachandran Chidambaram, Kennedy Brian P, Asante-Appiah Ernest
Merck Research Laboratory, P. O. Box 2000, Rahway, New Jersey 07065, USA.
Biochemistry. 2003 Oct 7;42(39):11451-9. doi: 10.1021/bi035098j.
Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here 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 near the 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 molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.
蛋白酪氨酸磷酸酶1B（PTP1B）与胰岛素信号通路的调节有关，是设计2型糖尿病和肥胖症治疗抑制剂的一个有吸引力的靶点。对PTP1B结构的研究表明，通过靶向二级芳基磷酸结合位点以及催化位点，可能获得有效的PTP1B抑制剂。我们在此报告了PTP1B与第一代和第二代芳基二氟甲基膦酸抑制剂复合物的晶体结构。虽然所有化合物都结合在靠近主要结合位点的一个以前未被利用的结合口袋中，但第二代化合物还延伸到二级结合位点，并且对PTP1B的选择性高于密切相关的T细胞磷酸酶。通过在52位进行单点突变证实了选择性的分子基础，这两种磷酸酶在该位置因苯丙氨酸到酪氨酸的转换而不同。这些化合物为开发有效的选择性PTP1B抑制剂提供了一个新的平台。
