Structures of human PTP1B variants reveal allosteric sites to target for weight loss therapy.

ABSTRACT: Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of leptin signaling whose disruption protects against diet-induced obesity in mice. We investigated whether structural characterization of human PTP1B variant proteins might reveal allosteric sites to target for weight loss therapy. To do so, we selected 12 rare variants for functional characterization from exomes from 997 people with persistent thinness and 200,000 people from UK Biobank. Seven of 12 variants impaired PTP1B function by increasing leptin-stimulated STAT3 phosphorylation in human cells. Focusing on the variants in and near the ordered catalytic domain, we ascribed structural mechanism to their functional effects using in vitro enzyme activity assays, room-temperature X-ray crystallography, and local hydr

SUBMITTER: Perdikari A 

PROVIDER: S-EPMC11326154 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature