Title: Superagonistic fluorinated vitamin d(3) analogs stabilize helix 12 of the vitamin d receptor
Authors: Eelen, Guy *
Valle, Noelia *
Sato, Yoshiteru
Rochel, Natacha
Verlinden, Lieve
De Clercq, Pierre
Moras, Dino
Bouillon, Roger
Muñoz, Alberto
Verstuyf, Annemieke # ×
Issue Date: Oct-2008
Publisher: Current Biology Ltd.
Series Title: Chemistry & Biology vol:15 issue:10 pages: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.
ISSN: 1074-5521
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
* (joint) first author
× corresponding author
# (joint) last author

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