All over the world, diabetes mellitus type 2 has spread as a problematic pandemic. Despite currently available treatments, approved drugs still show undesirable side effects and loss of efficacy or target symptoms instead of causes. Protein tyrosine phosphatase 1B (PTP1B), since its discovery, has emerged as a very promising target against this disease. Although the information regarding the enzyme is immense, little is known about the selectivity between this enzyme and its closest homologue, lymphocyte T tyrosine phosphatase (TCPTP), which is responsible for complicated side effects. In this study, on the basis of different computational approaches, we are able to highlight the importance of a phenylalanine residue located in PTP1B, but not in TCPTP, as a crucial hotspot that causes selectivity and stability for the whole ligand bound system. These results not only allow to explain the selectivity determinants of PTP1B but also provide a useful guide for the design of new allosteric inhibitors.

Communicated by Ramaswamy H. Sarma

在世界各地，2型糖尿病已成为大流行病的蔓延。尽管目前有可用的治疗方法，但批准的药物仍然显示出不良的副作用以及功效或目标症状的丧失，而不是原因。自发现以来，蛋白质酪氨酸磷酸酶1B（PTP1B）已成为对抗这种疾病的非常有希望的靶标。尽管有关该酶的信息非常丰富，但对该酶与其最接近的同源物淋巴细胞T酪氨酸磷酸酶（TCPTP）之间的选择性知之甚少，这是造成复杂副作用的原因。在这项研究中，基于不同的计算方法，我们能够突出显示PTP1B中而不是TCPTP中的苯丙氨酸残基的重要性，因为它是导致整个配体结合系统选择性和稳定性的关键热点。

由Ramaswamy H.Sarma沟通