Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.

Autor:	Krishnan N; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Bonham CA; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Rus IA; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.; Graduate Program in Genetics and Medical Scientist Training Program, Stony Brook University, 100 Nicolls Road, Stony Brook, NY, 11794, USA., Shrestha OK; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Gauss CM; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Haque A; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Tocilj A; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.; W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.; Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Joshua-Tor L; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.; W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.; Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Tonks NK; Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA. tonks@cshl.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Jan 18; Vol. 9 (1), pp. 283. Date of Electronic Publication: 2018 Jan 18.
DOI:	10.1038/s41467-017-02252-2
Abstrakt:	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.
Databáze:	MEDLINE
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