5vf6

Publication Abstract from PubMed

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.

Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.,Krishnan N, Bonham CA, Rus IA, Shrestha OK, Gauss CM, Haque A, Tocilj A, Joshua-Tor L, Tonks NK Nat Commun. 2018 Jan 18;9(1):283. doi: 10.1038/s41467-017-02252-2. PMID:29348454^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.