Structural Analysis of VDR Complex with ZK168281 Antagonist

J Med Chem. 2020 Sep 10;63(17):9457-9463. doi: 10.1021/acs.jmedchem.0c00656. Epub 2020 Aug 20.

Abstract

Vitamin D receptor (VDR) antagonists prevent the VDR activation function helix 12 from folding into its active conformation, thus affecting coactivator recruitment and antagonizing the transcriptional regulation induced by 1α,25-dihydroxyvitamin D3. Here, we report the crystal structure of the zebrafish VDR ligand-binding domain in complex with the ZK168281 antagonist, revealing that the ligand prevents optimal folding of the C-terminal region of VDR. This interference was confirmed by hydrogen-deuterium exchange mass spectrometry (HDX-MS) in solution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitriol / analogs & derivatives*
  • Calcitriol / metabolism
  • Calcitriol / pharmacology
  • Cell Line
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Domains
  • Rats
  • Receptors, Calcitriol / antagonists & inhibitors*
  • Receptors, Calcitriol / chemistry
  • Receptors, Calcitriol / metabolism*
  • Zebrafish

Substances

  • Ligands
  • Receptors, Calcitriol
  • ZK 168281
  • Calcitriol