Journal
CHEMISTRY & BIOLOGY
Volume 15, Issue 10, Pages 1029-1034Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2008.08.008
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Funding
- Fonds voor Wetenschappelijk Onderzoek (FWO) [G-0508.05, G.0553.06]
- NucSys (EU Marie Curie RTN)
- Ministeno de Educacion y Ciencia [SAF2007-60341]
- Ministerio de Sanidad y Consumo of Spain [RD06/0020/0009]
- European Commission [QLG2-CT-220-0098, LSHG-CT-2006-031220]
- CNRS
- INSERM
- ULP
- RTICC [RD06/0020/0009]
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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 Va1444 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.
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