Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3

Pierre Antony (1, 2) , Rita Sigüeiro , Tiphaine Huet , Yoshiteru Sato , Nick Ramalanjaona , Luis Rodrigues , Antonio Mouriño , Dino Moras (2, 1) , Natacha Rochel (2, 1)

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (2a) acts as a 1 alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D(3), 2 alpha-methyl-1 alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.

Domaines: Biochimie, Biologie Moléculaire

Pierre Antony, Rita Sigüeiro, Tiphaine Huet, Yoshiteru Sato, Nick Ramalanjaona, et al.. Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3. Journal of Medicinal Chemistry, 2010, 53 (3), pp.1159-1171. ⟨10.1021/jm9014636⟩. ⟨hal-04089573⟩