PMID- 15728261
OWN - NLM
STAT- MEDLINE
DCOM- 20050615
LR  - 20191210
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 67
IP  - 5
DP  - 2005 May
TI  - Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by 
      vitamin D receptor-coactivator interaction.
PG  - 1566-73
AB  - Two 14-epi-analogs of 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D(3)], 
      19-nor-14-epi-23-yne-1,25-(OH)2D3 (TX522) and 
      19-nor-14,20-bisepi-23-yne-1,25-(OH)2D3 (TX527), show enhanced antiproliferative 
      (at least 10-fold) and markedly lower calcemic effects both in vitro and in vivo, 
      compared with 1,25-(OH)2D3. This study aimed to evaluate their superagonistic 
      effect at the level of interaction between the Vitamin D receptor (VDR) and 
      coactivators. Mammalian two-hybrid assays with VP16-fused VDR and 
      GAL4-DNA-binding-domain-fused steroid receptor coactivator 1 (SRC-1), 
      transcriptional intermediary factor 2 (Tif2), or DRIP205 showed the 
      14-epi-analogs to be more potent inducers of VDR-coactivator interactions than 
      1,25-(OH)2D3 (up to 16- and 20-fold stronger induction of VDR-SRC-1 interaction 
      for TX522 and TX527 at 10(-10) M). Similar assays in which metabolism of 
      1,25-(OH)2D3 was blocked with VID400, a selective inhibitor of the 
      1,25-(OH)2D3-metabolizing enzyme CYP24, showed that the enhanced potency of these 
      analogs in establishing VDR-coactivator interactions can only partially be 
      accounted for by their increased resistance to metabolic degradation. 
      Crystallization of TX522 complexed to the ligand binding domain of the human VDR 
      demonstrated that the epi-configuration of C14 caused the CD ring of the ligand 
      to shift by 0.5 angstroms, thereby bringing the C12 atom into closer contact with 
      Val300. Moreover, C22 of TX522 made an additional contact with the CD1 atom of 
      Ile268 because of the rigidity of the triple bond-containing side chain. The 
      position and conformation of the activation helix H12 of VDR was strictly 
      maintained. In conclusion, this study provides deeper insight into the docking of 
      TX522 in the LBP and shows that stronger VDR-coactivator interactions underlie 
      the superagonistic activity of the two 14-epi-analogs.
FAU - Eelen, Guy
AU  - Eelen G
AD  - Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke 
      Universiteit Leuven, Belgium.
FAU - Verlinden, Lieve
AU  - Verlinden L
FAU - Rochel, Natacha
AU  - Rochel N
FAU - Claessens, Frank
AU  - Claessens F
FAU - De Clercq, Pierre
AU  - De Clercq P
FAU - Vandewalle, Maurits
AU  - Vandewalle M
FAU - Tocchini-Valentini, Giuseppe
AU  - Tocchini-Valentini G
FAU - Moras, Dino
AU  - Moras D
FAU - Bouillon, Roger
AU  - Bouillon R
FAU - Verstuyf, Annemieke
AU  - Verstuyf A
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050222
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Receptors, Calcitriol)
RN  - 1406-16-2 (Vitamin D)
RN  - 66772-14-3 (1,25-dihydroxyvitamin D)
SB  - IM
MH  - Animals
MH  - Binding Sites/drug effects/physiology
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Receptors, Calcitriol/*agonists/*metabolism
MH  - Vitamin D/*analogs & derivatives/chemistry/*metabolism/pharmacology
EDAT- 2005/02/25 09:00
MHDA- 2005/06/16 09:00
CRDT- 2005/02/25 09:00
PHST- 2005/02/25 09:00 [pubmed]
PHST- 2005/06/16 09:00 [medline]
PHST- 2005/02/25 09:00 [entrez]
AID - mol.104.008730 [pii]
AID - 10.1124/mol.104.008730 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2005 May;67(5):1566-73. doi: 10.1124/mol.104.008730. Epub 2005 Feb 
      22.