Allosteric Activation of Striatal-Enriched Protein Tyrosine Phosphatase (STEP, PTPN5) by a Fragment-like Molecule

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 15N 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.

非受体型蛋白酪氨酸磷酸酶5（Protein tyrosine phosphatase non-receptor type 5，简称PTPN5，又称STEP）是一种脑特异性磷酸酶，可通过调控N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptor，简称NMDAR）与α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor，简称AMPAR）的转运，调节突触功能与突触可塑性。STEP的表达失调与神经退行性疾病及神经精神疾病密切相关，这使得该酶成为药物研发领域极具吸引力的治疗靶点。然而，由于蛋白酪氨酸磷酸酶家族活性位点的高度保守性，利用小分子选择性靶向STEP的研究一直受到阻碍。本研究报道了首个结合于STEP磷酸酶结构域（phosphatase domain）的小分子变构激活剂（allosteric activator）。其变构结合特性通过X射线晶体衍射实验与15N核磁共振实验得到验证，酶学级联检测实验证实了该化合物的特异性。分子动力学模拟结果显示，该化合物通过远距离变构机制增强了STEP的酶促活性。为便于科研群体使用这一研究工具，我们将通过开放创新计划提供该化合物以供研究使用。