3A2J

Crystal structure of the human vitamin D receptor (H305F/H397F) ligand binding domain complexed with TEI-9647

Summary for 3A2J

• Entry DOI: 10.2210/pdb3a2j/pdb
• Related: 3A2H 3A2I
• Descriptor: Vitamin D3 receptor, (1S,3R,5Z,7E,20S,23S)-1,3-dihydroxy-23,26-epoxy-9,10-secocholesta-5,7,10,25(27)-tetraen-26-one (3 entities in total)
• Functional Keywords: hormone/growth factor receptor, dna-binding, metal-binding, nucleus, phosphoprotein, transcription, transcription regulation, zinc-finger, activator, disease mutation, receptor, hormone receptor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P11473
• Total number of polymer chains: 1
• Total formula weight: 30249.98

Authors

Kakuda, S.,Takimoto-Kamimura, M. (deposition date: 2009-05-20, release date: 2010-05-26, Last modification date: 2023-11-01)

Primary citation

Kakuda, S.,Ishizuka, S.,Eguchi, H.,Mizwicki, M.T.,Norman, A.W.,Takimoto-Kamimura, M.
Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone
Acta Crystallogr.,Sect.D, 66:918-926, 2010

PubMed Abstract: 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.

PubMed: 20693691
DOI: 10.1107/S0907444910020810

Experimental method

X-RAY DIFFRACTION (2.7 Å)