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Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor.

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.
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https://www.hal.inserm.fr/inserm-00350744
Contributor : Maité Peney <>
Submitted on : Tuesday, February 3, 2009 - 3:45:33 PM
Last modification on : Sunday, November 29, 2020 - 10:24:02 AM

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Guy Eelen, Noelia Valle, Yoshiteru Sato, Natacha Rochel, Lieve Verlinden, et al.. Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor.. Chemistry & Biology / Chemistry and Biology; CHEMISTRY & BIOLOGY, 2008, 15 (10), pp.1029-34. ⟨10.1016/j.chembiol.2008.08.008⟩. ⟨inserm-00350744⟩

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