Vitamin D Receptor:  Ligand Recognition and Allosteric Network

Yamamoto, Keiko; Abe, Daijiro; Yoshimoto, Nobuko; Choi, Mihwa; Yamagishi, Kazumasa; Tokiwa, Hiroaki; Shimizu, Masato; Makishima, Makoto; Yamada, Sachiko

doi:10.1021/jm050795q

Cited by 52 publications

(84 citation statements)

References 40 publications

(102 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2B). As expected, 7,19) VDR activation by 1,25(OH) 2 D 3 and LCA was abolished by mutation of residues necessary for ligand binding (R274A, H305A and H397A) (Figs. 2C, D).…”

Section: 7)supporting

confidence: 80%

“…17) cDNA were synthesized using an ImProm- Figure 2A. 7,9) Protein expression of all VDR mutants was detected in HEK293 cells with immunoblotting using anti-VDR and anti-FLAG antibodies (Fig. 2B).…”

Section: 7)mentioning

confidence: 99%

“…[6][7][8] A statistical coupling analysis has demonstrated that RXR heterodimer allosteric communication is required for effective activation of VDR by LCA but not by 1,25(OH) 2 D 3 . 9) Indeed, LCA induces the interaction of VDR with RXR, steroid receptor coactivator 1 (SRC-1), and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) in a manner distinct from 1,25(OH) 2 D 3 in cells.…”

mentioning

confidence: 99%

“…3,5) Lithocholic acid (LCA), a secondary bile acid, acts as an additional physiological VDR ligand and interacts with the VDR ligand-binding pocket in a mode distinct from 1,25(OH) 2 D 3 , and alternate contacts are seen particularly with helices 3 and 4/5, components of the AF2 surface. [6][7][8] A statistical coupling analysis has demonstrated that RXR heterodimer allosteric communication is required for effective activation of VDR by LCA but not by 1,25(OH) 2 D 3 .…”

mentioning

confidence: 99%

See 3 more Smart Citations

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Chuma

Endo-Umeda

Shimba

et al. 2012

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

1) VDR acts as an allosteric transcription factor that undergoes a ligand-dependent conformational change in the cofactor binding site and activation function 2 (AF2) domain, structural rearrangements that result in dynamic interaction with the heterodimer partner retinoid X receptor (RXR; NR2B) and exchange of cofactor complexes.2,3) While corepressors bind to the VDR-RXR heterodimer in the absence of ligand, the ligand binding reduces the affinity of corepressors and increases the affinity for coactivators, a structural transition that induces transcription of specific genes. The VDR-RXR heterodimer binds preferentially to a DNA response element that consists of a two hexanucleotide (AGGTCA or a related sequence) direct repeat motif separated by three nucleotides (DR3).4) The DR3 VDRbinding element has been identified in the regulatory regions of many target genes, including cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), cathelicidin antimicrobial peptide (CAMP), and osteopontin.2,4) An everted repeat of the hexanucleotide motif separated by six nucleotides (ER6) is another VDR-binding element that regulates expression of the human CYP3A4 gene.2) Dynamic and coordinated interactions of VDR with RXR and cofactor complexes are required for the efficient regulation of transcription.3,5) Lithocholic acid (LCA), a secondary bile acid, acts as an additional physiological VDR ligand and interacts with the VDR ligand-binding pocket in a mode distinct from 1,25(OH) 2 D 3 , and alternate contacts are seen particularly with helices 3 and 4/5, components of the AF2 surface. [6][7][8] A statistical coupling analysis has demonstrated that RXR heterodimer allosteric communication is required for effective activation of VDR by LCA but not by 1,25(OH) 2 D 3 . 9) Indeed, LCA induces the interaction of VDR with RXR, steroid receptor coactivator 1 (SRC-1), and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) in a manner distinct from 1,25(OH) 2 D 3 in cells.3)Although the role of VDR in mediating the biological effects of 1,25(OH) 2 D 3 has been investigated for decades, an understanding of the biology of VDR regulation by LCA is only now emerging.Hairless (HR) is a nuclear protein that functions as a corepressor of nuclear receptors, including thyroid hormone receptor, retinoic acid receptor-related orphan receptors and VDR.10-12) HR interacts with VDR via multiple protein-protein interfaces in the absence of ligand and represses VDR transactivation by 1,25(OH) 2 D 3 and LCA.12,13) Interestingly, LCA but not 1,25(OH) 2 D 3 enhances the interaction, 12) suggesting that LCA induces a conformation of the VDR-RXR heterodimer with enhanced affinity for HR binding. In both mice and humans, mutation of HR results in hair-loss phenotypes similar to VDR mutation, suggesting a functional interaction of HR and VDR in vivo. 14) In contrast to the in vitro interaction, 1,25(OH) 2 D 3 treatment decreases HR binding to VDR in keratinocytes. 15) Although the in vivo role of HR in VDR function remains ...

show abstract

“…2B). As expected, 7,19) VDR activation by 1,25(OH) 2 D 3 and LCA was abolished by mutation of residues necessary for ligand binding (R274A, H305A and H397A) (Figs. 2C, D).…”

Section: 7)supporting

confidence: 80%

Section: 7)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Chuma

Endo-Umeda

Shimba

et al. 2012

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ab initio FMO method has been applied in large biochemical systems for quantum chemical analysis to molecular interaction [40][41][42][43][44][45]. In this method, HA-sialoside complex is divided into fragments, and MO calculations are carried out on each fragment and fragment pairs.…”

Section: Introductionmentioning

confidence: 99%

Ab initio fragment molecular orbital studies of influenza virus hemagglutinin–sialosaccharide complexes toward chemical clarification about the virus host range determination

et al. 2008

Self Cite

View full text Add to dashboard Cite

If we predict the host range of new or mutant influenza virus in advance, we are able to measure against pandemic human influenza immediately after the new virus emerges somewhere. Influenza viral hemagglutinin(HA)-sialoside receptor interaction is a target event for in silico chemical prediction studies about the virus host range determination. We theoretically studied avian and human influenza A virus HA H3 subtype complexed with avian or human type receptor Neu5Acα(2-3 or 2-6)Gal analogues by ab initio fragment molecular orbital (FMO) method at the second order Møller-Plesset (MP2)/6-31G level, which can evaluate correctly not only electrostatic interactions but also lipophilic interactions based on van der Waals dispersion force. Avian H3 bound to avian α2-3 11.4 kcal/mol stronger than to human α2-6 in the model complexes with taking account of intermolecular lipophilic interaction. A substitution at the position 226 between Gln (avian) and Leu(human) on influenza H3 HA1 has altered Glycoconj J (2008) its virus host range between avian and human. In the ab initio FMO studies, binding energy of avian Gln226Leu H3-human α2-6 was quite similar to that in the human H3-human α2-6 complex with amino acid sequence differences at nine positions in the models. This similarity indicates that avian Gln226Leu H3 virus can infect human with the same level as human H3 virus. Opposite mutation Leu226Gln in the human H3 gave the moderate binding energies to avian α2-3 with similarity to avian H3-α2-3 complex that supported our previous virus-sialoside binding assay. Ab initio FMO studies have revealed the relationship between influenza H3 virus host range and H3-α(2-3 or 2-6) receptors binding. Our theoretical approach may predict the infectious level of new viruses and point out some unknown dangerous mutation positions on HA in advance.

show abstract

Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

2007

View full text Add to dashboard Cite

The fragment molecular orbital (FMO) method has enabled electronic structure calculations and geometry optimizations of very large molecules with ab initio quality. We applied the method to four FK506 binding protein (FKBP) complexes (denoted by their PDB codes 1fkb, 1fkf, 1fkg, and 1fki) containing rapamycin, FK506, and two synthetic ligands. The geometries of reduced complex models were optimized at the restricted Hartree-Fock (FMO-RHF) level using the 3-21G basis set, and then for a better estimate of binding, the energetics were refined at a higher level of theory (2nd order Møller-Plesset perturbation theory FMO-MP2 with the 6-31G* basis set). Thus, obtained binding energies were -103.9 (-82.0), -102.2 (-69.2), -70.1 (-57.7), and -71.3 (-55.3) kcal/mol for 1fkb, 1fkf, 1fkg, and 1fki, respectively, where the correlation contribution is given in parentheses. The results show that the electron correlation contribution to binding is extremely important, and it accounts for 70-80% of the binding energy. The molecular recognition mechanism of FKBP was analyzed in detail based on the FMO-pair interactions between protein residues and the ligands. Solvation effects on the protein-ligand binding were estimated using the Poisson-Boltzmann/surface area model.

show abstract

Vitamin D Receptor: Ligand Recognition and Allosteric Network

Cited by 52 publications

References 40 publications

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Ab initio fragment molecular orbital studies of influenza virus hemagglutinin–sialosaccharide complexes toward chemical clarification about the virus host range determination

Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

Contact Info

Product

Resources

About