2zfx | pdb_00002zfx
Crystal structure of the rat vitamin D receptor ligand binding domain complexed with YR301 and a synthetic peptide containing the NR2 box of DRIP 205
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 PubMedVitamin 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 AlsoReferences
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