Barr Alastair J, Knapp Stefan
Structural Genomics Consortium, University of Oxford, Botnar Research Centre, Oxford, OX3 7LD, UK.
Trends Pharmacol Sci. 2006 Oct;27(10):525-30. doi: 10.1016/j.tips.2006.08.005. Epub 2006 Aug 21.
Protein tyrosine phosphatases (PTPs) have key roles in a diverse range of cellular processes, and their dysregulation is associated with several human diseases. Many PTPs are recognized as potential drug targets; however, inhibitor development has focused only on a small number of enzymes, most notably PTP1B for type II diabetes and obesity, and MKP1 and CDC25 for cancer. The future challenge of selective-inhibitor development for PTPs will be significantly facilitated by the recent rapid progress in the structural biology of the 'PTPome'. In this article, we focus on the family of mitogen-activated protein kinase (MAPK)-specific tyrosine phosphatases--PTPN5 [also called striatal-enriched phosphatase (STEP)], PTPN7 (also called hematopoietic PTP) and PTPRR (also called PC12 PTP or STEP-like PTP)--and discuss approaches for achieving selectivity for the MAPK-PTPs at the molecular level using recently determined high-resolution X-ray crystal structures. We believe that the development of specific inhibitors would provide a valuable set of experimental pharmacological tools for investigating the physiological role of these phosphatases and exploring their emerging role in human disease.
蛋白质酪氨酸磷酸酶（PTPs）在多种细胞过程中发挥关键作用，其失调与多种人类疾病相关。许多PTPs被认为是潜在的药物靶点；然而，抑制剂开发仅集中在少数几种酶上，最显著的是用于治疗II型糖尿病和肥胖症的PTP1B，以及用于治疗癌症的MKP1和CDC25。“PTPome”结构生物学最近的快速进展将极大地推动未来PTPs选择性抑制剂开发的挑战。在本文中，我们聚焦于丝裂原活化蛋白激酶（MAPK）特异性酪氨酸磷酸酶家族——PTPN5[也称为富含纹状体的磷酸酶（STEP）]、PTPN7（也称为造血PTP）和PTPRR（也称为PC12 PTP或类STEP PTP）——并讨论利用最近确定的高分辨率X射线晶体结构在分子水平上实现对MAPK-PTPs选择性的方法。我们相信，特异性抑制剂的开发将为研究这些磷酸酶的生理作用以及探索它们在人类疾病中的新作用提供一套有价值的实验药理学工具。
