4G1D: Structural basis for the accommodation of bis- and tris-aromatic derivatives in Vitamin D Nuclear Receptor

Actual use of the active form of vitamin D (calcitriol or 1alpha,25-dihydroxyvitamin D(3)) to treat hyperproliferative disorders is hampered by calcemic effects, hence the continuous development of chemically modified analogues with dissociated profiles. Structurally distinct nonsecosteroidal analogues have been developed to mimic calcitriol activity profiles with low calcium serum levels. Here, we report the crystallographic study of vitamin D nuclear receptor (VDR) ligand binding domain in complexes with six nonsecosteroidal analogues harboring two or three phenyl rings. These compounds induce a stimulated transcription in the nanomolar range, similar to calcitriol. Examination of the protein-ligand interactions reveals the mode of binding of these nonsecosteroidal compounds and highlights the role of the various chemical modifications of the ligands to VDR binding and activity, notably (de)solvation effects. The structures with the tris-aromatic ligands exhibit a rearrangement of a novel region of the VDR ligand binding pocket, helix H6.
PDB ID: 4G1DDownload
MMDB ID: 103358
PDB Deposition Date: 2012/7/10
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 2.9  Å
Source Organism:
Danio rerio
Similar Structures:
Biological Unit for 4G1D: dimeric; determined by author and by software (PISA)
Molecular Components in 4G1D
Label Count Molecule
Proteins (2 molecules)
Vitamin D3 Receptor a(Gene symbol: vdra)
Molecule annotation
Nuclear Receptor Coactivator 1(Gene symbol: NCOA1)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB