Department of Molecular Immunology , Beckman Research Institute of the City of Hope , 1500, E. Duarte Road , Duarte , California 91010 , United States.
J Med Chem. 2019 Jan 10;62(1):306-316. doi: 10.1021/acs.jmedchem.8b00857. Epub 2018 Sep 12.
Protein tyrosine phosphatase non-receptor type 5 (PTPN5, STEP) is a brain specific phosphatase that regulates synaptic function and plasticity by modulation of N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Dysregulation of STEP has been linked to neurodegenerative and neuropsychiatric diseases, highlighting this enzyme as an attractive therapeutic target for drug discovery. Selective targeting of STEP with small molecules has been hampered by high conservation of the active site among protein tyrosine phosphatases. We report the discovery of the first small molecule allosteric activator for STEP that binds to the phosphatase domain. Allosteric binding is confirmed by both X-ray and N NMR experiments, and specificity has been demonstrated by an enzymatic test cascade. Molecular dynamics simulations indicate stimulation of enzymatic activity by a long-range allosteric mechanism. To allow the scientific community to make use of this tool, we offer to provide the compound in the course of an open innovation initiative.
蛋白酪氨酸磷酸酶非受体型 5（PTPN5，STEP）是一种脑特异性磷酸酶，通过调节 N-甲基-D-天冬氨酸受体（NMDAR）和 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的转运来调节突触功能和可塑性。STEP 的失调与神经退行性和神经精神疾病有关，这凸显了该酶作为药物发现有吸引力的治疗靶点。由于蛋白酪氨酸磷酸酶的活性位点高度保守，因此使用小分子选择性靶向 STEP 一直受到阻碍。我们报告了第一个 STEP 的小分子别构激活剂的发现，该激活剂与磷酸酶结构域结合。通过 X 射线和 N NMR 实验证实了别构结合，并且通过酶促测试级联证明了特异性。分子动力学模拟表明，通过远程别构机制刺激酶活性。为了使科学界能够利用这一工具，我们提出在开放创新倡议的过程中提供该化合物。
