Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.
Navasona KrishnanChristopher A BonhamIoana A RusOm Kumar ShresthaCarla M GaussAftabul HaqueAnte TociljLeemor Joshua-TorNicholas K TonksPublished in: Nature communications (2018)
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.
Keyphrases
- type diabetes
- glycemic control
- small molecule
- insulin resistance
- randomized controlled trial
- cardiovascular disease
- metabolic syndrome
- weight loss
- low density lipoprotein
- blood glucose
- molecular dynamics simulations
- high fat diet induced
- signaling pathway
- transcription factor
- skeletal muscle
- machine learning
- oxidative stress
- nitric oxide
- drug induced
- diabetic rats
- crystal structure
- artificial intelligence
- protein kinase