| Structural highlights
Function
[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
Vitamin D receptor (VDR) is a ligand-inducible hormone receptor that mediates 1alpha,25(OH)(2)D(3) action, regulating calcium and phosphate metabolism, induces potent cell differentiation activity and has immunosuppressive effects. Analogues of 1alpha,25(OH)(2)D(3) have been used clinically for some years. However, the risk of potential side effects limits the use of these substances. LG190178 is a novel nonsecosteroidal ligand for VDR. (2S)-3-[4-(3-{4-[(2R)-2-hydroxy-3,3-dimethylbutoxy]-3-methylphenyl}pentan- 3-yl)-2-methylphenoxy] propane-1,2-diol (YR301) is the only one of the four evaluated stereoisomers of LG190178 to have strong activity. To understand the strong activity of YR301, the crystal structure of YR301 complexed with the rat VDR ligand-binding domain (VDR LBD) was solved at 2.0 A resolution and compared with the structure of the VDR LBD-1alpha,25(OH)(2)D(3) complex. YR301 and 1alpha,25(OH)(2)D(3) share the same position and the diethylmethyl group occupies a similar space to the C and D rings of 1alpha,25(OH)(2)D(3). YR301 has two characteristic hydroxyl groups which contribute to its potent activity. The first is 2'-OH, which forms hydrogen bonds to the NE2 atoms of both His301 and His393. The other is 2-OH, which interacts with Ser233 OG and Arg270 NH1. These two hydroxyl groups of YR301 correspond exactly to 25-OH and 1-OH, respectively, of 1alpha,25(OH)(2)D(3). The terminal hydroxyl group (3-OH) of YR301 is directly hydrogen bonded to Arg270 and also interacts indirectly with Tyr232 OH and the backbone NH of Asp144 via water molecules. Additional derivatization of the terminal hydroxyl group using the positions of the water molecules might be useful for the design of more potent compounds.
Structure of the ligand-binding domain of rat VDR in complex with the nonsecosteroidal vitamin D3 analogue YR301.,Kakuda S, Okada K, Eguchi H, Takenouchi K, Hakamata W, Kurihara M, Takimoto-Kamimura M Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Nov 1;64(Pt, 11):970-3. Epub 2008 Oct 31. PMID:18997319[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vanhooke JL, Tadi BP, Benning MM, Plum LA, DeLuca HF. New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations. Arch Biochem Biophys. 2007 Apr 15;460(2):161-5. Epub 2006 Dec 12. PMID:17227670 doi:10.1016/j.abb.2006.11.029
- ↑ 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
- ↑ Wang Q, Sharma D, Ren Y, Fondell JD. A coregulatory role for the TRAP-mediator complex in androgen receptor-mediated gene expression. J Biol Chem. 2002 Nov 8;277(45):42852-8. Epub 2002 Sep 5. PMID:12218053 doi:10.1074/jbc.M206061200
- ↑ Ge K, Guermah M, Yuan CX, Ito M, Wallberg AE, Spiegelman BM, Roeder RG. Transcription coactivator TRAP220 is required for PPAR gamma 2-stimulated adipogenesis. Nature. 2002 May 30;417(6888):563-7. PMID:12037571 doi:10.1038/417563a
- ↑ Kang YK, Guermah M, Yuan CX, Roeder RG. The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2642-7. Epub 2002 Feb 26. PMID:11867769 doi:10.1073/pnas.261715899
- ↑ Coulthard VH, Matsuda S, Heery DM. An extended LXXLL motif sequence determines the nuclear receptor binding specificity of TRAP220. J Biol Chem. 2003 Mar 28;278(13):10942-51. Epub 2003 Jan 29. PMID:12556447 doi:10.1074/jbc.M212950200
- ↑ Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG. Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha. Mol Cell. 2003 Nov;12(5):1137-49. PMID:14636573
- ↑ 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
- ↑ Malik S, Guermah M, Yuan CX, Wu W, Yamamura S, Roeder RG. Structural and functional organization of TRAP220, the TRAP/mediator subunit that is targeted by nuclear receptors. Mol Cell Biol. 2004 Sep;24(18):8244-54. PMID:15340084 doi:10.1128/MCB.24.18.8244-8254.2004
- ↑ 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
- ↑ Udayakumar TS, Belakavadi M, Choi KH, Pandey PK, Fondell JD. Regulation of Aurora-A kinase gene expression via GABP recruitment of TRAP220/MED1. J Biol Chem. 2006 May 26;281(21):14691-9. Epub 2006 Mar 30. PMID:16574658 doi:M600163200
- ↑ Kakuda S, Okada K, Eguchi H, Takenouchi K, Hakamata W, Kurihara M, Takimoto-Kamimura M. Structure of the ligand-binding domain of rat VDR in complex with the nonsecosteroidal vitamin D3 analogue YR301. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Nov 1;64(Pt, 11):970-3. Epub 2008 Oct 31. PMID:18997319 doi:http://dx.doi.org/10.1107/S1744309108026754
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