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Structural Analysis of VDR Complex with ZK168281 Antagonist
Anna Y Belorusova1,2,3,4,5, Sandra Chalhoub1,2,3,4, Daniela Rovito1,2,3,4
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, France.
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.
Insights
Vitamin D receptor (VDR) antagonists block VDR activation by preventing helix 12 folding. Structural and solution studies reveal how ZK168281 disrupts VDR
Area of Science:
- Molecular biology
- Structural biology
- Biochemistry
Background:
- Vitamin D receptor (VDR) antagonists inhibit VDR transcriptional regulation.
- VDR antagonists function by preventing the activation function helix 12 from adopting its active conformation.
Purpose of the Study:
- To elucidate the structural mechanism by which the VDR antagonist ZK168281 inhibits VDR function.
- To investigate the impact of ZK168281 on VDR C-terminal region folding.
Main Methods:
- X-ray crystallography of the zebrafish VDR ligand-binding domain in complex with ZK168281.
- Hydrogen-deuterium exchange mass spectrometry (HDX-MS) in solution.
Main Results:
- The crystal structure reveals that ZK168281 binding prevents the optimal folding of the VDR C-terminal region.
- HDX-MS confirmed that the antagonist interferes with VDR C-terminal region folding in solution.
Conclusions:
- ZK168281 antagonizes VDR transcriptional activity by disrupting the conformational flexibility of the VDR C-terminal region.
- Understanding these structural interactions provides insights into VDR antagonist design.
