Superagonistic Fluorinated Vitamin D3 Analogs Stabilize Helix 12 of the Vitamin D Receptor

被引：38

作者：

Eelen, Guy ^{[1
]}

Valle, Noelia ^{[2
]}

Sato, Yoshiteru ^{[3
]}

Rochel, Natacha ^{[3
]}

Verlinden, Lieve ^{[1
]}

De Clercq, Pierre ^{[4
]}

Moras, Dino ^{[3
]}

Bouillon, Roger ^{[1
]}

Munoz, Alberto ^{[2
]}

Verstuyf, Annemieke ^{[1
]}

机构：

[1] Katholieke Univ Leuven, LEGENDO, B-3000 Louvain, Belgium

[2] Univ Autonoma Madrid, CSIC, Inst Invest Biomed Alberto Sols, E-28029 Madrid, Spain

[3] Dept Biol & Genom Struct, IGBMC, F-67400 Illkirch Graffenstaden, France

[4] Univ Ghent, Vakgroep Organ Chem, B-9000 Ghent, Belgium

来源：

CHEMISTRY & BIOLOGY | 2008年 / 15卷 / 10期

关键词：

D O I：

10.1016/j.chembiol.2008.08.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1029 / 1034

页数：6

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