Exploring the allosteric mechanism of protein tyrosine phosphatase 1B by molecular dynamics simulations.

Protein tyrosine phosphatase 1B (PTP1B): a validated therapeutic target for type 2 diabetes and obesity. Since PTP1B was discovered in 1988, tremendous efforts have been made in finding its inhibitor, but so far, no inhibitor has been used for clinical treatment. In this study, molecular dynamics (MD) simulations were performed to study the binding mechanism of active site inhibitor (TCS401) and allosteric inhibitors (benzofuran compounds), and explore the connection between the active site and allosteric site. The results show that there is a hydrogen bond network (THR177-TYR152-ASN193-GLU297) connecting the active site and allosteric site. This hydrogen bond network is an important factor to maintain the WPD loop open or close and act as a signal propagation pathway to transfer the structure changes. ASN193 is the pivotal residue as it could connect key regions loop L11 and helix? 7. In addition, the dual dissociation state of TCS401 has a superior binding affinity to PTP1B than other states. Our study reveals a potential allosteric regulatory mechanism of PTP1B, which could give a new insight for the design of new allosteric inhibitors.