Abstract
The protein tyrosine phosphatase PTP1B is a major regulator of glucose homeostasis and energy metabolism, and a validated target for therapeutic intervention in diabetes and obesity. Nevertheless, it is a challenging target for inhibitor development. Previously, we generated a recombinant antibody (scFv45) that recognizes selectively the oxidized, inactive conformation of PTP1B. Here, we provide a molecular basis for its interaction with reversibly oxidized PTP1B. Furthermore, we have identified a small molecule inhibitor that mimics the effects of scFv45. Our data provide proof-of-concept that stabilization of PTP1B in an inactive, oxidized conformation by small molecules can promote insulin and leptin signaling. This work illustrates a novel paradigm for inhibiting the signaling function of PTP1B that may be exploited for therapeutic intervention in diabetes and obesity.
Highlights
The protein tyrosine phosphatase PTP1B is a major regulator of glucose homeostasis and energy metabolism, and a validated target for therapeutic intervention in diabetes and obesity
The protein tyrosine phosphatase PTP1B, which is a negative regulator of insulin and leptin signaling, is a highly validated target for therapeutic intervention in diabetes and obesity[3,4]
Insulin resistance can result in hepatic fat accumulation, which is a significant contributor to non-alchoholic steatohepatitis (NASH)[10,11]
Summary
Molecular basis for the interaction between scFv45 and PTP1B-OX. Reversible oxidation of PTP1B is accompanied by profound conformational changes in the protein, in the active site[18,19]. The two compounds that were confirmed hits from the LOPAC 1280 library screen, sanguinarine and levamisole, were docked using Schrödinger’s Glide module with the unique potential binding site of PTP1B-OX that was predicted by SiteMap. Interestingly, sanguinarine, but not levamisole, appeared to form a π-stacking interaction with Tyr[46], perhaps accounting for its stronger ability to prevent reduction of PTP1B-OX to the active form of the enzyme (Supplementary Fig. 10a, b). The orientation of Lys[36] may be critical for chelerythrine binding to PTP1B-OX (Fig. 5d) These data suggest that the chelerythrinebinding site in PTP1B overlaps with that of scFv45 and provide an explanation for the observed selectivity of the compound for the oxidized form of the phosphatase
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