Crystal structure of the rat vitamin D receptor ligand binding domain complexed with TEI-9647 and a synthetic peptide containing the NR2 box of DRIP 205
3a2h is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[VDR_RAT] Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Recruited to promoters via its interaction with the WINAC complex subunit BAZ1B/WSTF, which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.[1] [MED1_HUMAN] Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.[2][3][4][5][6][7][8][9][10][11][12]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone.,Kakuda S, Ishizuka S, Eguchi H, Mizwicki MT, Norman AW, Takimoto-Kamimura M Acta Crystallogr D Biol Crystallogr. 2010 Aug;66(Pt 8):918-26. Epub 2010, Jul 10. PMID:20693691[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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↑Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG. The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7939-44. PMID:9653119
↑Zhang J, Fondell JD. Identification of mouse TRAP100: a transcriptional coregulatory factor for thyroid hormone and vitamin D receptors. Mol Endocrinol. 1999 Jul;13(7):1130-40. PMID:10406464
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↑Wu Q, Burghardt R, Safe S. Vitamin D-interacting protein 205 (DRIP205) coactivation of estrogen receptor alpha (ERalpha) involves multiple domains of both proteins. J Biol Chem. 2004 Dec 17;279(51):53602-12. Epub 2004 Oct 5. PMID:15471764 doi:10.1074/jbc.M409778200
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↑Zhang X, Krutchinsky A, Fukuda A, Chen W, Yamamura S, Chait BT, Roeder RG. MED1/TRAP220 exists predominantly in a TRAP/ Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription. Mol Cell. 2005 Jul 1;19(1):89-100. PMID:15989967 doi:10.1016/j.molcel.2005.05.015
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↑Kakuda S, Ishizuka S, Eguchi H, Mizwicki MT, Norman AW, Takimoto-Kamimura M. Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone. Acta Crystallogr D Biol Crystallogr. 2010 Aug;66(Pt 8):918-26. Epub 2010, Jul 10. PMID:20693691 doi:10.1107/S0907444910020810
