Model of Three-Dimensional Structure of Vitamin D Receptor and Its Binding Mechanism With 1a,25-

ABSTRACT Comparative modeling of the vita-min D receptor three-dimensional structure and computational docking of 1a,25-dihydroxyvitamin D3 into the putative binding pocket of the two deletion mutant receptors: (207–423) and (120–422, D [164–207]) are reported and evaluated in the context of extensive mutagenic analysis and crystal structure of holo hVDR deletion protein published recently. The obtained molecular model agrees well with the experimentally determined structure. Six different conformers of 1a,25-dihydroxyvitamin D3 were used to study flexible docking to the receptor. On the basis of values of conformational energy of various complexes and their consistency with func-tional activity, it appears that 1a,25-dihydroxyvita-min D3 binds the receptor in its 6-s-trans form. The two lowest energy complexes obtained from dock-ing the hormone into the deletion protein (207–423) differ in conformation of ring A and orientation of the ligand molecule in the VDR pocket. 1a,25-Dihydroxyvitamin D3 possessing the A-ring confor-mation with axially oriented 1a-hydroxy group binds receptor with its 25-hydroxy substituent oriented toward the center of the receptor cavity, whereas ligand possessing equatorial conformation of 1a-hydroxy enters the pocket with A ring directed inward. The latter conformation and orientation of the ligand is consistent with the crystal structure of hVDR deletion mutant (118–425, D [165–215]). The lattice model of rVDR (120–422, D [164–207]) shows excellent agreement with the crystal structure of the hVDR mutant. The complex obtained from dock-ing the hormone into the receptor has lower energy than complexes for which homology modeling was used. Thus, a simple model of vitamin D receptor with the first two helices deleted can be potentially useful for designing a general structure of ligand, whereas the advanced lattice model is suitable for examining binding sites in the pocket. Protein