Structural Analysis of VDR Complex with ZK168281 Antagonist

Anna y Belorusova (1) , Sandra Chalhoub (1) , Daniela Rovito (1) , Natacha Rochel (1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Domaines: Biologie structurale [q-bio.BM]

Anna y Belorusova, Sandra Chalhoub, Daniela Rovito, Natacha Rochel. Structural Analysis of VDR Complex with ZK168281 Antagonist. Journal of Medicinal Chemistry, 2020, 63 (17), pp.9457 - 9463. ⟨10.1021/acs.jmedchem.0c00656⟩. ⟨hal-03032831⟩