A Conserved Local Structural Motif Controls the Kinetics of PTP1B Catalysis.

ABSTRACT: Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin signaling pathways, making it a highly attractive target for the treatment of type II diabetes. For PTP1B to perform its enzymatic function, a loop referred to as the "WPD loop" must transition between open (catalytically incompetent) and closed (catalytically competent) conformations, which have both been resolved by X-ray crystallography. Although prior studies have established this transition as the rate-limiting step for catalysis, the transition mechanism for PTP1B and other PTPs has been unclear. Here we present an atomically detailed model of WPD loop transitions in PTP1B based on unbiased, long-timescale molecular dynamics simulations and weighted ensemble simulations. We found that a specific

SUBMITTER: Yeh CY 

PROVIDER: S-EPMC10336961 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature