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

AuthorsEelen, Guy; Valle, Noelia ; Muñoz Terol, Alberto ; Verstuyf, Annemieke
Issue Date2008
CitationChemistry and Biology 15(10): 1029-1034 (2008)
AbstractSide 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 β-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. © 2008 Elsevier Ltd. All rights reserved.
DescriptionThis is an article Open Access.-- et al.
Publisher version (URL)http://dx.doi.org/10.1016/j.chembiol.2008.08.008
Identifiersdoi: 10.1016/j.chembiol.2008.08.008
issn: 1074-5521
e-issn: 1879-1301
Appears in Collections:(IIBM) Artículos
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