PDB 3CS6 deposited: 2008-04-09 modified: 2009-02-24
Title Structure-based design of a superagonist ligand for the vitamin D nuclear receptor
Authors Antony, P., Ciesielski, F., Hourai, S., Magnier, B.C., Moras, D., Mourino, A., Reina-San-Martin, B., Rochel, N., Rodrigues, L.C., Schoonjans, K.
Structure factors resolution 1.8 rfactor 0.192 rfree 0.206
DPI 0.28 theoretical min: 0.13
Related PDB Entries 3CS4

Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator, is an important target for multiple clinical applications, such as osteoporosis and cancer. Since exacerbated increase of calcium serum level is currently associated with VDR ligands action, superagonists with low calcium serum levels have been developed. Based on the crystal structures of human VDR (hVDR) bound to 1alpha,25-dihydroxyvitamin D(3) and superagonists-notably, KH1060-we designed a superagonist ligand. In order to optimize the aliphatic side chain conformation with a subsequent entropy benefit, we incorporated an oxolane ring and generated two stereo diasteromers, AMCR277A and AMCR277B. Only AMCR277A exhibits superagonist activity in vitro, but is as calcemic in vivo as the natural ligand. The crystal structures of the complexes between the ligand binding domain of hVDR and these ligands provide a rational approach to the design of more potent superagonist ligands for potential clinical application.

Chem.Biol. 2008 Apr; 15(4):383-392 doi:10.1016/j.chembiol.2008.03.016

Cross References
Database source Identifier Description
PubMed 18420145 CBOLE2
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3CS6/0 3CS6 0 monomer 0 1 1 2056