Regulation of the vitamin D receptor by vitamin D lactam derivatives

Abstract

The active metabolite of vitamin D 3 , 1a,25-dihydroxyvitamin D 3 , acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1a,25-dihydroxyvitamin D 3 -26,23-lactams (DLAMs), which mimic vitamin D 3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation. Since VDR activated by 1,25(OH) 2 D 3 coordinates calcium absorption in the gut and bone remodeling to maintain adequate serum calcium concentrations, this ligand-dependent receptor function is important to prevent rickets, osteomalacia, and hypocalcemic tetany [6]. Thus, many 1,25(OH) 2 D 3 derivatives have been developed as drug candidates for these diseases [7][8][9]. However, VDR activation by high-dose treatment with those types of ligands leads to excessive skeletal calcium release, increases intestinal calcium absorption, and decreases renal calcium excretion, thereby resulting in lethal levels of calcium in the bloodstream, known as hypercalcemia [10].We developed a new type of ligand, 1a,25-dihydroxyvitamin D 3 -26,23-lactams (DLAMs), which

Structural Analysis of VDR Complex with ZK168281 Antagonist

“…Due to weak affinity for corepressor peptides 13 or non-optimal crystal packing, only crystals of the complex in the presence of the SRC1 coactivator peptide NR2 (RHKILHRLLQEGS) were obtained and analyzed (Supplementary Table 1). These results are in agreement with previous reports characterizing X-ray structures of VDR complexes in presence of antagonist ligands [14][15][16][17][18][19] . ZK168281 binds to the VDR LBP unambiguously as shown by the POLDER omit map (Figure 1B).…”

“…Several crystal structures of VDR LBD complexes with antagonists have been previously reported, all crystalized in presence of a coactivator peptide [14][15][16][17][18][19] . Among them, the complexes with adamantyl 14 and 22S-butyl combined with 25 p-hydroxyphenyl 17 .…”

Discovery of Nuclear Receptor Ligands and Elucidation of Their Mechanisms of Action

“…Structure That Destabilizes Helix 6-7 Vitamin D analogues 23a, b-27a, b were designed and synthesized, and their biological activity was evaluated, so as to develop strong VDR antagonists based on the mechanism of inhibition of helix 12 folding caused by the bulky side chain of the ligand. This study demonstrated that the 25-dibenzyl analogues 24a and 24b both function as potent VDR antagonists 29) (Fig. 7).…”

Vitamin D and Its Synthetic Analogs

“…This further emphasizes the impact of vitamin D and VDR for innate and adaptive immunity and suggests that these areas should be further explored for a commercial application …”

“…The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00208. Table S1 describing all 143 publically available VDR ligand crystal structures with individual hyperlinks to the PDB and PubMed databases and citations of refs − (PDF) …”