PUBLICATION
Structural insights into the molecular mechanism of Vitamin D Receptor activation by lithocholic acid involving a new mode of ligand recognition
- Authors
- Belorusova, A.Y., Eberhardt, J., Potier, N., Stote, R., Dejaegere, A., Rochel, N.
- ID
- ZDB-PUB-140514-10
- Date
- 2014
- Source
- Journal of medicinal chemistry 57(11): 4710-9 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- Calorimetry
- Crystallography, X-Ray
- Humans
- Ligands
- Lithocholic Acid/chemistry*
- Molecular Dynamics Simulation
- Mutation
- Protein Binding
- Protein Conformation
- Receptors, Calcitriol/agonists*
- Receptors, Calcitriol/chemistry
- Receptors, Calcitriol/metabolism
- Spectrometry, Mass, Electrospray Ionization
- Thermodynamics
- Transfection
- Zebrafish
- Zebrafish Proteins/agonists*
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/metabolism
- PubMed
- 24818857 Full text @ J. Med. Chem.
Citation
Belorusova, A.Y., Eberhardt, J., Potier, N., Stote, R., Dejaegere, A., Rochel, N. (2014) Structural insights into the molecular mechanism of Vitamin D Receptor activation by lithocholic acid involving a new mode of ligand recognition. Journal of medicinal chemistry. 57(11):4710-9.
Abstract
The vitamin D receptor (VDR), an endocrine nuclear receptor for 1α,25-dihydroxyvitamin D3, acts also as a bile acid sensor by binding the lithocholic acid (LCA). The crystal structure of the zebrafish VDR ligand binding domain in complex with LCA and the SRC-2 coactivator peptide reveals the binding of two LCA molecules by VDR. One LCA binds to the canonical ligand-binding pocket and the second one, which is not fully buried, is anchored to a site located on the VDR surface. Despite the low affinity of the alternate site, the binding of the second molecule promotes stabilization of the active receptor conformation. Biological activity assays, structural analysis and molecular dynamics simulations indicate that the recognition of two ligand molecules is crucial for VDR agonism by LCA. The unique binding mode of LCA provides clues for the development of new chemical compounds that target alternate binding sites for therapeutic applications.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping