PUBLICATION
Superagonistic fluorinated vitamin D(3) analogs stabilize helix 12 of the vitamin D receptor
- Authors
- Eelen, G., Valle, N., Sato, Y., Rochel, N., Verlinden, L., De Clercq, P., Moras, D., Bouillon, R., Muñoz, A., and Verstuyf, A.
- ID
- ZDB-PUB-081028-9
- Date
- 2008
- Source
- Chemistry & Biology 15(10): 1029-1034 (Journal)
- Registered Authors
- Keywords
- CHEMBIOL, SIGNALING
- MeSH Terms
-
- Protein Structure, Tertiary
- Models, Molecular
- Humans
- Crystallography, X-Ray
- beta Catenin/genetics
- Cell Line, Tumor
- TCF Transcription Factors/genetics
- Protein Structure, Secondary
- Binding Sites
- Transcription, Genetic/drug effects
- Transcription, Genetic/genetics
- Receptors, Calcitriol/chemistry*
- Receptors, Calcitriol/genetics
- Receptors, Calcitriol/metabolism*
- Cell Differentiation/drug effects
- Cholecalciferol/agonists*
- Cholecalciferol/analogs & derivatives*
- Cholecalciferol/chemistry
- Fluorine Compounds/agonists*
- Fluorine Compounds/chemistry
- PubMed
- 18940664 Full text @ Chem. Biol.
Citation
Eelen, G., Valle, N., Sato, Y., Rochel, N., Verlinden, L., De Clercq, P., Moras, D., Bouillon, R., Muñoz, A., and Verstuyf, A. (2008) Superagonistic fluorinated vitamin D(3) analogs stabilize helix 12 of the vitamin D receptor. Chemistry & Biology. 15(10):1029-1034.
Abstract
Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] resistant to degradation by 24-hydroxylase. The fluorinated nonsteroidal analogs CD578, WU515, and WY1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of beta-catenin/TCF activity. Cocrystallization of analog CD578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD578 make additional contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD578 complex than with the VDR-1,25(OH)(2)D(3) complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping