Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B
Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B
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DOI：
10.1016/s1097-2765(00)00137-4
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发表时间：
2000-12-01
期刊：
影响因子：
16
通讯作者：
Barford, D
中科院分区：
文献类型：
--
作者：
Salmeen, A;Andersen, JN;Barford, D
蛋白酪氨酸磷酸酶PTP1B通过使胰岛素受体激酶(Irk)激活片段的磷酸酪氨酸残基去磷酸化来负向调节胰岛素信号。在这里，通过结合结晶学、动力学和PTP1B肽结合研究，我们定义了该反应的分子特异性。PTP1B与包含串联pTyr残基的1162和1163处的IRK序列之间形成广泛的相互作用，使得pTyr-1162被选择在催化部位，而pTyr-1163位于相邻的pTyr识别部位。这种选择性归因于串联pTyr多肽比单一pTyr多肽的亲和力高70倍，并预测了一个分层的去磷酸化过程。PTP1B-IRK相互作用的许多元素是PTP1B独有的，这表明产生这种相互作用的特异性小分子抑制剂用于治疗糖尿病和肥胖症可能是可行的。
The protein tyrosine phosphatase PTP1B is responsible for negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase (IRK) activation segment. Here, by integrating crystallographic, kinetic, and PTP1B peptide binding studies, we define the molecular specificity of this reaction. Extensive interactions are formed between PTP1B and the IRK sequence encompassing the tandem pTyr residues at 1162 and 1163 such that pTyr-1162 is selected at the catalytic site and pTyr-1163 is located within an adjacent pTyr recognition site. This selectivity is attributed to the 70-fold greater affinity for tandem pTyr-containing peptides relative to mono-pTyr peptides and predicts a hierarchical dephosphorylation process. Many elements of the PTP1B-IRK interaction are unique to PTP1B, indicating that it may be feasible to generate specific, small molecule inhibitors of this interaction to treat diabetes and obesity.