Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain

Yamamoto, Keiko; Masuno, Hiroyuki; Choi, Mihwa; Nakashima, Kinichi; Taga, Tetsuya; Ooizumi, Hiroshi; Umesono, Kazuhiko; Sicińska, Wanda; Vanhooke, Janeen L.; DeLuca, Hector F.; Yamada, Sachiko

doi:10.1073/pnas.020522697

Cited by 72 publications

(69 citation statements)

References 33 publications

(30 reference statements)

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“…1 and 7A) were adapted to the available space within the receptor by bending their side chains. This is in agreement with recently published data (Yamamoto et al, 2000;Tocchini-Valentini et al, 2001). The A-ring of the ligands was always similarly positioned in the ligand binding pocket and the CD-ring showed only a slight variation in its positioning.…”

supporting

confidence: 83%

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

et al. 2002

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The crystal structures of the ligand binding domain of human vitamin D receptor (VDR) complexed with its natural ligand or the superagonists MC1288 or KH1060 have recently been reported. The crystallized ligand binding domain (LBD) of VDR, however, differs from the full-length VDR with respect to deletion of 50 amino acids between its helices 2 and 3. In this study, we investigated structurally and functionally important amino acid interactions within the ligand binding pocket of the fulllength VDR in the presence of several synthetic vitamin D 3 analogs. We used site-directed mutagenesis scanning combined with limited proteolytic digestion, electrophoretic mobility shift assay, and reporter gene assay and correlated the findings with the crystal structures of truncated VDR LBD. Our results suggest that structurally different agonists have distinct ligandreceptor interactions and that the amino acid residues H229, D232, E269, F279, and Y295 are critical for the agonistic conformation of the VDR. Our biological data, which were obtained with the full-length VDR, fit well with the crystal structure of the truncated VDR LBD and suggest that removal of the insertion domain between helices 2 and 3 of the receptor does not markedly influence the functionality of the VDR.The biologically active form of vitamin D 3 , 1␣,25-dihydroxyvitamin D 3 (calcitriol), regulates several important physiological and biochemical functions in mammals, such as calcium and phosphorus homeostasis as well as cellular growth, differentiation, and apoptosis (DeLuca et al., 1990;Walters, 1992). Binding of calcitriol to its receptor (VDR) induces a conformational change in the receptor and promotes formation of a heterodimer with retinoid X receptor (RXR) as well as binding of other transcriptional cofactors to the receptor. The VDR-RXR heterodimer attaches to a specific segment of DNA, the vitamin D response element (VDRE), which is located in the promoter regions of calcitriol target genes (Carlberg, 1995(Carlberg, , 1996Toell et al., 2000).The VDR belongs to the nuclear receptor superfamily. Many members of this superfamily have conserved amino acid sequences in the C terminus of the receptor (Wurtz et al., 1996;Haussler et al., 1998). VDR, however, makes an exception in that it has a long, unordered loop structure between helices 2 and 3. The LBDs of several nuclear receptors have already been successfully crystallized (Bourguet et al., 1995;Renaud et al., 1995;Wagner et al., 1995;Brzozowski et al., 1997;Williams and Sigler, 1998;Pike et al., 1999;Gampe et al., 2000;Egea et al., 2000;Clayton et al., 2001;Watkins et al., 2001), and a clear homology can be observed in their three-dimensional structures because they share a common helical sandwich structure with three layers of ␣-helices surrounding the hydrophobic ligand binding pocket. When the crystal structure of truncated VDR LBD was solved by Rochel et al. (2000), it could be observed that VDR does not make an exception to the structural principles of related receptors. However,...

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confidence: 83%

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

et al. 2002

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“…The diluted lysate was incubated with 1 nM of [26,27-methyl-3 H]1,25(OH)2D3 for 16 h at 4 Њ C in the presence or absence of nonradioactive competing compounds (14). Bound and free compounds were separated by the dextran-charcoal method (17). Bound and labeled 1,25(OH)2D3 was quantitated using scintillation counting.…”

Section: Competitive Ligand Binding Assaymentioning

confidence: 99%

Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative

Adachi

Honma

Masuno

et al. 2005

Journal of Lipid Research

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These differences in ligand-receptor interaction may contribute to the differential recruitment of coactivators to VDR and selective biological actions (7).Nuclear receptors are ligand-inducible transcription factors that are involved in many biological processes, including cell growth and differentiation, embryonic development, and metabolic homeostasis (8). Recently, nuclear receptors belonging to the NR1H and NR1I subfamilies, including VDR, have been shown to control cholesterol Abbreviations: BSEP, bile salt export pump; CAR, constitutive androstane receptor; ER, estrogen receptor; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein;

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“…Recently, we proposed a three-dimensional model of a liganded VDR-LBD constructed by the homology modeling technique in conjunction with mutation studies to substantiate the model. 11) The crystal structure of a deletion mutant (D 165-215) of VDR-LBD complexed with 1a,25-(OH) 2 D 3 was also reported recently by Moras et al 12) Our model closely resembles the X-ray structure except for some details. In the crystal structure the A-ring of 1 adopts the bconformation, while in our model we assumed the a-form.…”

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confidence: 51%

(10Z)- and (10E)-19-Fluoro-1.ALPHA.,25-dihydroxyvitamin D3. An Improved Synthesis via 19-Nor-10-oxo-vitamin D.

Shimizu

Ohno

Yamada

2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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As a physiologically active form of vitamin D 3 , 1a, 2 D 3 ; 1] regulates calcium and phosphate homeostasis and is also involved in controlling cellular growth, differentiation and apoptosis.1) The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily that regulates gene expression in response to binding of their specific ligands. Ligand binding stabilizes the transcriptionally active conformation of the ligand binding domain of the receptors, 2) enabling the recruitment of coactivators and results in either gene transactivation or repression depending on the target gene.It is critical for better understanding the molecular mechanism of gene expression by 1 to clarify the 3-dimensional structure of 1 bound to VDR. 1a,25-(OH) 2 D 3 1 is a highly flexible molecule and can adopt a number of conformations around the A-ring, seco-B-ring, and side chain. In a series of systematic studies on conformation-function relationship of vitamin D, we have proposed a concept of the active side chain space region of vitamin D using systematic conformational analysis and conformationally-restricted analogs as tools.3-6) Our research interests have also been directed to the A-ring and the conjugated triene part of 1. The A-ring conformation of vitamin D is thought to be essential for the recognition of the active site of the VDR ligand binding cavity. In solution, vitamin D exists as an approximate equimolar mixture of rapidly equilibrating A-ring chair conformers, designated as a-and b-forms, according to 1 H-NMR analysis (Chart 1). 7) Worldwide controversy concerning which conformation is responsible for VDR binding has continued for a long time. The crystal structures of ligand-binding domains (LBD) of numerous nuclear receptors including a retinoic acid receptor, 2,8) thyroid hormone receptor 9) and estrogen receptor 10) have recently been solved. However, the crystal structure of the wild type VDR-LBD has not been solved. Recently, we proposed a three-dimensional model of a liganded VDR-LBD constructed by the homology modeling technique in conjunction with mutation studies to substantiate the model.11) The crystal structure of a deletion mutant (D 165-215) of VDR-LBD complexed with 1a,25-(OH) 2 D 3 was also reported recently by Moras et al. 12) Our model closely resembles the X-ray structure except for some details. In the crystal structure the A-ring of 1 adopts the bconformation, while in our model we assumed the a-form.In our studies to investigate dynamics of the conformation of vitamin D in VDR/vitamin D complex, in particular the A-ring and the triene moieties, by 19 F-NMR spectroscopy, we have reported syntheses of 19-fluoro-1a,25-dihydroxyvitamin D 3 (2 and 3) and 4,4-difluoro-1a,25-dihydroxyvitamin D 3 as probe compounds (Charts 1 and 2). [13][14][15] In the synthesis of 2 and 3, an electrophilic fluorination of a vitamin D-SO 2 adduct (II) was used as a key step. The difficulties in this synthesis are 1) electrophilic fluorination of the SO 2 adduct (II) is not satisfactory and 2) desulfonylat...

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Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain

Cited by 72 publications

References 33 publications

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

Structurally and Functionally Important Amino Acids of the Agonistic Conformation of the Human Vitamin D Receptor

Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative

(10Z)- and (10E)-19-Fluoro-1.ALPHA.,25-dihydroxyvitamin D3. An Improved Synthesis via 19-Nor-10-oxo-vitamin D.

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