A Structural Basis for the Species-Specific Antagonism of 26,23-Lactones on Vitamin D Signaling Original Research Article

The 26,23-lactone derivative of 1α,25-dihydroxyvitamin D3, TEI-9647, is a partial antagonist of the of human vitamin D receptor (VDR). However, we found that TEI-9647 in rat cells behaves as a weak VDR agonist. This behavior could be mimicked in human cells by the double mutagenesis of human VDR (specifically C403S and C410N). The increased agonistic action of TEI-9647 correlates to a gain in the interaction of the VDR with coactivator protein and a decreased stabilization of the antagonistic conformation of the receptor. Molecular dynamics simulations indicated that TEI-9647 acts as antagonist of human VDR by reducing the stability of helix 12 of the ligand binding domain. In contrast, N410 of the rat VDR stabilized, via backbone contacts, the interaction between helices 11 and 12. This results in TEI-9647 becoming a weak agonist in this organism.