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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Developing Adnectins that target SRC co-activator binding to PXR: a structural approach toward understanding

Javed A Khan1, Daniel M Camac1, Simon Low2

  • 1Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.

Journal of Molecular Biology
|January 13, 2015
PubMed

Insights

Researchers developed Adnectins, which block the pregnane X receptor (PXR) from interacting with coactivator SRC-1. These Adnectins maintain the binding of other compounds, offering new structural insights and therapeutic potential.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • The human pregnane X receptor (PXR) is a nuclear receptor that senses xenobiotics and regulates drug-metabolizing enzymes and transporters.
  • PXR plays a crucial role in drug metabolism and detoxification pathways.

Purpose of the Study:

  • To develop novel molecules (Adnectins) targeting the PXR ligand binding domain (LBD) and its interaction with steroid receptor coactivator-1 (SRC-1).
  • To elucidate the structural basis of Adnectin binding to PXR and its impact on coactivator interaction and ligand binding.

Main Methods:

  • Generation of Adnectins derived from the 10th fibronectin type III domain ((10)Fn3).
  • Determination of co-crystal structures of PXR LBD with Adnectin-1 and a CCR1 antagonist (Compound-1).
  • Structural analysis to understand the molecular interactions at the PXR-SRC-1 interface.

Main Results:

  • Adnectins were shown to displace SRC-1 binding to the PXR LBD.
  • Co-crystal structures revealed that Adnectin-1 specifically targets the SRC-1 interaction interface on PXR.
  • Adnectin-1 binding did not alter the conformation of Compound-1 within the PXR ligand binding pocket.
  • Structural data facilitated modulation of PXR affinity for a related CCR1 antagonist.

Conclusions:

  • Adnectins represent a novel class of PXR modulators that specifically disrupt coactivator recruitment.
  • The determined structures provide valuable insights into PXR-ligand and PXR-coactivator interactions.
  • Adnectins show potential as tools for structural studies of PXR and as therapeutic agents, including use as crystallization chaperones.
Keywords:
AdnectinCCR1PXRSRC-1nuclear receptor

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