PDB 2HB7 deposited: 2006-06-14 modified: 2009-02-24
Title Crystal structure of VDR LBD in complex with 2alpha(3-hydroxy-1-propyl) calcitriol
Authors Fujishima, T., Hourai, S., Kittaka, A., Moras, D., Rochel, N., Suhara, Y., Takayama, H.
Structure factors resolution 1.8 rfactor 0.187 rfree 0.204
DPI 0.27 theoretical min: 0.13
Related PDB Entries 2HAM 2HAR 2HAS 2HB8

The crystal structure of the vitamin D receptor (VDR) in complex with 1 alpha,25(OH)2D3 revealed the presence of several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, we report the crystal structures of the human VDR ligand binding domain bound to selected C-2 alpha substituted analogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacements do not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, all analogues affect the presence and/or the location of the above water molecules. The integrity of the channel interactions and specific C-2 alpha analogue directed additional interactions correlate with the binding affinity of the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 cell differentiation. Our overall findings highlight a rational approach to the design of more potent ligands by building in features revealed in the crystal structures.

J.Med.Chem. 2006 Aug; 49(17):5199-5205 doi:10.1021/jm0604070

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1146844
PubMed 16913708 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
2HB7/0 2HB7 0 monomer 0 1 1 2047