Relationship between Structure and Conformational Change of the Vitamin D Receptor Ligand Binding Domain in 1α,25-Dihydroxyvitamin D3 Signaling

Abstract

Vitamin D Receptor (VDR) belongs to the nuclear receptor (NR) superfamily. Whereas the structure of the ligand binding domain (LBD) of VDR has been determined in great detail, the role of its amino acid residues in stabilizing the structure and ligand triggering conformational change is still under debate. There are 13 α-helices and one β-sheet in the VDR LBD and they form a three-layer sandwich structure stabilized by 10 residues. Thirty-six amino acid residues line the ligand binding pocket (LBP) and six of these residues have hydrogen-bonds linking with the ligand. In 1α,25-dihydroxyvitamin D 3 signaling, H3 and H12 play an important role in the course of conformational change resulting in the provision of interfaces for dimerization, coactivator (CoA), corepressor (CoR), and hTAF II 28. In this paper we provide a detailed description of the amino acid residues stabilizing the structure and taking part in conformational change of VDR LBD according to functional domains.

Calcitriol-mediated reduction in IFN-γ output in T cell large granular lymphocytic leukemia requires vitamin D receptor upregulation

“…To determine whether VDR upregulation is necessary to suppress IFN-γ and p-STAT1 levels, we utilized EB1089, a potent calcitriol analog, and 25(OH)D 3 , the inactive circulating form of vitamin D. EB1089 strongly engages the VDR and induces a conformational change that promotes transcription of VDR targets [44] while 25(OH)D 3 weakly interacts with the VDR [45]. Treatment with 25(OH)D 3 did not upregulate VDR protein (Figure 4A, 4B) but decreased p-STAT1 (Figure 4A, Figure 4C) in a manner comparable to calcitriol.…”

Genetic Causes of Rickets

“…It is well known that active vitamin D mediates its biological functions by binding to its receptor VDR, which contains an N-terminal dual zinc finger DNA binding domain, a C-terminal ligand-binding domain and an extensive and unstructured region that links the two functional domains together ( 15 ). After binding of vitamin D, VDR forms a ternary structure with RXRα, which binds to a VDRE in the promoter region of vitamin D-regulated genes to initiate transcription ( 37 , 38 ). Currently, there are 65 different mutations listed in HGMD (accessed Nov 13, 2017).…”

Revealing Unknown Protein Structures Using Computational Conformational Sampling Guided by Experimental Hydrogen-Exchange Data

“…The human vitamin D receptor (VDR) is a medium-sized protein composed of 427 amino acids, from the nuclear receptor superfamily. It can be functionally divided into four regions: a short amino terminus, a DNA-binding domain, a hinge domain and a ligand-binding domain (between residues 124 and 427) [ 44 ]. No structure of the whole protein has been so far reported in the PDB.…”

“…The molecule resulting from this deletion, which we simply refer to as VDR-LBD in this paper, is composed of 253 amino acids. Its structure consists of 12 -helices (usually denoted by H1–H12) folded into a three-layered antiparallel sandwich forming a hydrophobic binding pocket [ 44 ].…”