PDB 3A40 deposited: 2009-06-25 modified: 2013-11-20
Title Crystal structure of the human VDR ligand binding domain bound to the synthetic agonist compound 2alpha-methyl-AMCR277B(C23R)
Authors Antony, P., Huet, T., Moras, D., Mourino, A., Ramalanjaona, N., Rochel, N., Rodrigues, L.C., Sato, Y., Sigueiro, R.
Structure factors resolution 1.45 rfactor 0.16038 rfree 0.19556
DPI 0.18 theoretical min: 0.07
Related PDB Entries 3A3Z

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.

J.Med.Chem. 2010 Feb; 53(3):1159-1171 doi:10.1021/jm9014636

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1156853
PubMed 20070104 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3A40/0 3A40 0 monomer 0 1 3 2377