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

Aliki Perdikari1, Virgil A Woods2,3, Ali Ebrahim2

  • 1University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science & Addenbrooke's Hospital; Cambridge, CB2 0QQ, UK.

Biorxiv : the Preprint Server for Biology
|August 16, 2024
PubMed

Insights

Rare variants in Protein Tyrosine Phosphatase 1B (PTP1B) impair its function, revealing new allosteric sites. These findings offer potential targets for developing novel obesity treatments.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Genetics

Background:

  • Protein Tyrosine Phosphatase 1B (PTP1B) negatively regulates leptin signaling.
  • Inhibition of PTP1B has shown promise in preventing diet-induced obesity in mouse models.

Purpose of the Study:

  • To structurally characterize human PTP1B variants to identify allosteric sites for weight loss therapies.
  • To investigate the functional impact of rare PTP1B variants found in individuals with persistent thinness.

Main Methods:

  • Functional characterization of 12 rare PTP1B variants identified from human exomes.
  • In vitro enzyme activity assays, X-ray crystallography, and hydrogen-deuterium exchange mass spectrometry (HDX-MS).
  • Analysis of leptin-stimulated STAT3 phosphorylation in human cells.

Main Results:

  • Seven of 12 variants demonstrated impaired PTP1B function, leading to increased STAT3 phosphorylation.
  • Structural analysis revealed an inherent allosteric network in PTP1B distinct from known mechanisms.
  • Key variant sites were identified as highly ligandable surface areas.

Conclusions:

  • The identified allosteric network in PTP1B presents novel opportunities for drug design.
  • Targeted allosteric PTP1B inhibitors could be developed for effective obesity treatment.
  • Understanding PTP1B variant structures informs future therapeutic strategies for metabolic disorders.
Keywords:
HDX-MSPTP1BX-ray crystallographyallosteryhuman geneticshuman variantsphosphatasesprotein dynamics

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