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A natural-product switch for a dynamic protein interface.

Marcel Scheepstra1, Lidia Nieto, Anna K H Hirsch

  • 1Laboratory of Chemical Biology and Institute of Complex Molecular Systems (ICMS), Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven (The Netherlands) http://www.tue.nl/cb.

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Summary
This summary is machine-generated.

Researchers discovered a natural product that targets the retinoid X receptor (RXR) on both sides of its activation function 2 (AF2) interface. This led to developing a novel RXR agonist and a selective RXR/coactivator inhibitor.

Keywords:
drug discoverynatural productsnuclear receptorsprotein-protein interactionsretinoid X receptor

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Area of Science:

  • Molecular biology
  • Biochemistry
  • Structural biology

Background:

  • Small molecules regulate protein complex function through dynamic binding interfaces.
  • Nuclear receptors, like retinoid X receptor (RXR), are regulated by small ligands at the activation function 2 (AF2) interface, controlling gene transcription.
  • Existing ligands primarily target the ligand-binding pocket side of the AF2, with few options for selective coactivator-side targeting or switching.

Purpose of the Study:

  • To identify novel small molecules that can modulate the retinoid X receptor (RXR) at both sides of the activation function 2 (AF2) interface.
  • To develop selective RXR modulators by dissecting dual-activity compounds.
  • To explore the potential of natural products in targeting dynamic protein interfaces.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy and computational modeling to identify a dual-acting natural product targeting RXR.
  • Chemical synthesis to modify the natural product.
  • Cellular screening assays to evaluate compound activity.
  • X-ray co-crystallography to determine the structural basis of ligand-receptor interactions.

Main Results:

  • Identification of a natural product that binds to both the ligand-binding pocket and the coactivator-binding surface of the RXR AF2 interface.
  • Chemical synthesis and screening yielded a potent RXR agonist.
  • Development of a novel inhibitor selective for the RXR/coactivator interaction, a first-in-class compound.
  • Structural insights into how ligands can be designed to target different sides of the AF2 interface.

Conclusions:

  • Natural products can serve as valuable starting points for discovering ligands that target complex protein interfaces like the RXR AF2.
  • The ability to selectively target either side of the AF2 interface opens new avenues for drug development.
  • This study provides a blueprint for exploring other dynamic protein-protein interaction sites using natural product-derived chemical probes.