 |
PDBsum entry 4g20
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription/transcription inhibitor
|
PDB id
|
|
|
|
4g20
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for the accommodation of bis- And tris-Aromatic derivatives in vitamin d nuclear receptor.
|
|
|
Authors
|
|
F.Ciesielski,
Y.Sato,
Y.Chebaro,
D.Moras,
A.Dejaegere,
N.Rochel.
|
|
|
Ref.
|
|
J Med Chem, 2012,
55,
8440-8449.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Actual use of the active form of vitamin D (calcitriol or
1α,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.
|
|
|
|
|
|
|
