PDB 3A2I deposited: 2009-05-20 modified: 2010-08-18
Title Crystal structure of the human vitamin D receptor (H305F) ligand binding domain complexed with TEI-9647
Authors Eguchi, H., Ishizuka, S., Kakuda, S., Mizwicki, M.T., Norman, A.W., Takimoto-Kamimura, M.
Structure factors resolution 3.27 rfactor 0.21844 rfree 0.27578
DPI 1.57 theoretical min: 0.76
Related PDB Entries 3A2H 3A2J

TEI-9647 antagonizes vitamin D receptor (VDR) mediated genomic actions of 1alpha,25(OH)2D3 in human cells but is agonistic in rodent cells. The presence of Cys403, Cys410 or of both residues in the C-terminal region of human VDR (hVDR) results in antagonistic action of this compound. In the complexes of TEI-9647 with wild-type hVDR (hVDRwt) and H397F hVDR, TEI-9647 functions as an antagonist and forms a covalent adduct with hVDR according to MALDI-TOF MS. The crystal structures of complexes of TEI-9647 with rat VDR (rVDR), H305F hVDR and H305F/H397F hVDR showed that the agonistic activity of TEI-9647 is caused by a hydrogen-bond interaction with His397 or Phe397 located in helix 11. Both biological activity assays and the crystal structure of H305F hVDR complexed with TEI-9647 showed that the interaction between His305 and TEI-9647 is crucial for antagonist activity. This study indicates the following stepwise mechanism for TEI-9647 antagonism. Firstly, TEI-9647 forms hydrogen bonds to His305, which promote conformational changes in hVDR and draw Cys403 or Cys410 towards the ligand. This is followed by the formation of a 1,4-Michael addition adduct between the thiol (-SH) group of Cys403 or Cys410 and the exo-methylene group of TEI-9647.

Acta Crystallogr.,Sect.D 2010 Aug; 66(Pt 8):918-926 doi:10.1107/S0907444910020810

Cross References
Database source Identifier Description
PubMed 20693691 ABCRE6
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3A2I/0 3A2I 0 monomer 0 1 1 1866