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Superagonistic fluorinated vitamin D3 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
Verstuyf A
Source :
Chemistry & biology [Chem Biol] 2008 Oct 20; Vol. 15 (10), pp. 1029-34.
Publication Year :
2008

Abstract

Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] 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)2D3 complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.

Details

Language :
English
ISSN :
1074-5521
Volume :
15
Issue :
10
Database :
MEDLINE
Journal :
Chemistry & biology
Publication Type :
Academic Journal
Accession number :
18940664
Full Text :
https://doi.org/10.1016/j.chembiol.2008.08.008