Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Quercetin Directly Interacts with Vitamin D Receptor (VDR): Structural Implication of VDR Activation by Quercetin

  • Lee, Ki-Young (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Choi, Hye-Seung (Department of Molecular Science and Technology, Ajou University) ;
  • Choi, Ho-Sung (College of Pharmacy, Ajou University) ;
  • Chung, Ka Young (School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Bong-Jin (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University) ;
  • Maeng, Han-Joo (College of Pharmacy, Gachon University) ;
  • Seo, Min-Duk (Department of Molecular Science and Technology, Ajou University)
  • Received : 2015.08.07
  • Accepted : 2015.09.09
  • Published : 2016.03.01
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Abstract

The vitamin D receptor (VDR) is a member of the nuclear receptor (NR) superfamily. The VDR binds to active vitamin $D_3$ metabolites, which stimulates downstream transduction signaling involved in various physiological activities such as calcium homeostasis, bone mineralization, and cell differentiation. Quercetin is a widely distributed flavonoid in nature that is known to enhance transactivation of VDR target genes. However, the detailed molecular mechanism underlying VDR activation by quercetin is not well understood. We first demonstrated the interaction between quercetin and the VDR at the molecular level by using fluorescence quenching and saturation transfer difference (STD) NMR experiments. The dissociation constant ($K_d$) of quercetin and the VDR was $21.15{\pm}4.31{\mu}M$, and the mapping of quercetin subsites for VDR binding was performed using STD-NMR. The binding mode of quercetin was investigated by a docking study combined with molecular dynamics (MD) simulation. Quercetin might serve as a scaffold for the development of VDR modulators with selective biological activities.

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References

  1. Bartik, L., Whitfield, G. K., Kaczmarska, M., Lowmiller, C. L., Moffet, E. W., Furmick, J. K., Hernandez, Z., Haussler, C. A., Haussler, M. R. and Jurutka, P. W. (2010) Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. J. Nutr. Biochem. 21, 1153-1161. https://doi.org/10.1016/j.jnutbio.2009.09.012
  2. Belorusova, A. Y. and Rochel, N. (2014) Modulators of vitamin D nuclear receptor: recent advances from structural studies. Curr. Top. Med. Chem. 14, 2368-2377. https://doi.org/10.2174/1568026615666141208095937
  3. Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F. and Hermans, J. (1981) Interaction Models for Water in Relation to Protein Hydration. In Intermolecular Forces (B. Pullman, Ed.), Vol. 14, pp. 331-342. Springer Netherlands. https://doi.org/10.1007/978-94-015-7658-1_21
  4. Choi, M., Yamamoto, K., Itoh, T., Makishima, M., Mangelsdorf, D. J., Moras, D., DeLuca, H. F. and Yamada, S. (2003) Interaction between vitamin D receptor and vitamin D ligands: two-dimensional alanine scanning mutational analysis. Chem. Biol. 10, 261-270. https://doi.org/10.1016/S1074-5521(03)00050-4
  5. Choi, M., Yamamoto, K., Masuno, H., Nakashima, K., Taga, T. and Yamada, S. (2001) Ligand recognition by the vitamin D receptor. Bioorg. Med. Chem. 9, 1721-1730. https://doi.org/10.1016/S0968-0896(01)00060-8
  6. Darden, T., Perera, L., Li, L. and Pedersen, L. (1999) New tricks for modelers from the crystallography toolkit: the particle mesh Ewald algorithm and its use in nucleic acid simulations. Structure 7, R55-R60. https://doi.org/10.1016/S0969-2126(99)80033-1
  7. Duurkens, R. H., Tol, M. B., Geertsma, E. R., Permentier, H. P. and Slotboom, D. J. (2007) Flavin binding to the high affinity riboflavin transporter RibU. J. Biol. Chem. 282, 10380-10386. https://doi.org/10.1074/jbc.M608583200
  8. Feldman, D. and Malloy, P. J. (2014) Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets. BoneKEy Rep. 3. 510.
  9. Haussler, M. R., Jurutka, P. W., Mizwicki, M. and Norman, A. W. (2011) Vitamin D receptor (VDR)-mediated actions of 1alpha,25(OH)(2) vitamin D(3): genomic and non-genomic mechanisms. Best Pract. Res. Clin. Endocrinol. Metab. 25, 543-559. https://doi.org/10.1016/j.beem.2011.05.010
  10. Hess, B., Bekker, H., Berendsen, H. J. C. and Fraaije, J. G. E. M. (1997) LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463-1472. https://doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H
  11. Hess, B., Kutzner, C., van der Spoel, D. and Lindahl, E. (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput. 4, 435-447. https://doi.org/10.1021/ct700301q
  12. Inoue, J., Choi, J. M., Yoshidomi, T., Yashiro, T. and Sato, R. (2010) Quercetin enhances VDR activity, leading to stimulation of its target gene expression in Caco-2 cells. J. Nutr. Sci. Vitaminol. (Tokyo) 56, 326-330. https://doi.org/10.3177/jnsv.56.326
  13. Mayer, M. and Meyer, B. (2001) Group epitope mapping by saturation transfer difference NMR to identify segments of a ligand in direct contact with a protein receptor. J. Am. Chem. Soc. 123, 6108-6117. https://doi.org/10.1021/ja0100120
  14. Meyer, B. and Peters, T. (2003) NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angew. Chem. Int. Ed. Engl. 42, 864-890. https://doi.org/10.1002/anie.200390233
  15. Mizwicki, M. T., Menegaz, D., Yaghmaei, S., Henry, H. L. and Norman, A. W. (2010) A molecular description of ligand binding to the two overlapping binding pockets of the nuclear vitamin D receptor (VDR): structure-function implications. J. Steroid Biochem. Mol. Biol. 121, 98-105. https://doi.org/10.1016/j.jsbmb.2010.04.005
  16. Motoyoshi, S., Yamagishi, K., Yamada, S. and Tokiwa, H. (2010) Ligand-dependent conformation change reflects steric structure and interactions of a vitamin D receptor/ligand complex: a fragment molecular orbital study. J. Steroid Biochem. Mol. Biol. 121, 56-59. https://doi.org/10.1016/j.jsbmb.2010.03.024
  17. Rochel, N., Wurtz, J. M., Mitschler, A., Klaholz, B. and Moras, D. (2000) The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol. Cell 5, 173-179. https://doi.org/10.1016/S1097-2765(00)80413-X
  18. Russo, M., Spagnuolo, C., Tedesco, I., Bilotto, S. and Russo, G. L. (2012) The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem. Pharmacol. 83, 6-15. https://doi.org/10.1016/j.bcp.2011.08.010
  19. Schmid, N., Eichenberger, A. P., Choutko, A., Riniker, S., Winger, M., Mark, A. E. and van Gunsteren, W. F. (2011) Definition and testing of the GROMOS force-field versions 54A7 and 54B7. Eur. Biophys. J. 40, 843-856. https://doi.org/10.1007/s00249-011-0700-9
  20. Shimizu, M., Yamamoto, K., Mihori, M., Iwasaki, Y., Morizono, D. and Yamada, S. (2004) Two-dimensional alanine scanning mutational analysis of the interaction between the vitamin D receptor and its ligands: studies of A-ring modified 19-norvitamin D analogs. J. Steroid Biochem. Mol. Biol. 89-90, 75-81. https://doi.org/10.1016/j.jsbmb.2004.03.088
  21. Singarapu, K. K., Zhu, J., Tonelli, M., Rao, H., Assadi-Porter, F. M., Westler, W. M., DeLuca, H. F. and Markley, J. L. (2011) Ligandspecific structural changes in the vitamin D receptor in solution. Biochemistry 50, 11025-11033. https://doi.org/10.1021/bi201637p
  22. Stayrook, K. R., Carson, M. W., Ma, Y. L. and Dodge, J. A. (2011) Chapter 78 - Non-secosteroidal Ligands and Modulators. In Vitamin D (Third Edition) (D. F. W. P. S. Adams, Ed.), pp. 1497-1508. Academic Press, San Diego.
  23. Trott, O. and Olson, A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-461.
  24. Wang, K., Chen, S., Xie, W. and Wan, Y. J. (2008) Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway. Biochem. Pharmacol. 75, 2204-2213. https://doi.org/10.1016/j.bcp.2008.02.030
  25. Yamada, S. and Makishima, M. (2014) Structure-activity relationship of nonsecosteroidal vitamin D receptor modulators. Trends Pharmacol. Sci. 35, 324-337. https://doi.org/10.1016/j.tips.2014.04.008
  26. Yamagishi, K., Yamamoto, K., Yamada, S. and Tokiwa, H. (2006) Functions of key residues in the ligand-binding pocket of vitamin D receptor: Fragment molecular orbital-interfragment interaction energy analysis. Chem. Phys. Lett. 420, 465-468. https://doi.org/10.1016/j.cplett.2005.12.078
  27. Yamamoto, K., Anami, Y. and Itoh, T. (2014) Development of vitamin D analogs modulating the pocket structure of vitamin D receptor. Curr. Top. Med. Chem. 14, 2378-2387. https://doi.org/10.2174/156802661421141223091909
  28. Yamamoto, K., Choi, M., Abe, D., Shimizu, M. and Yamada, S. (2007) Alanine scanning mutational analysis of the ligand binding pocket of the human Vitamin D receptor. J. Steroid Biochem. Mol. Biol. 103, 282-285. https://doi.org/10.1016/j.jsbmb.2006.12.018
  29. Yamamoto, K., Masuno, H., Choi, M., Nakashima, K., Taga, T., Ooizumi, H., Umesono, K., Sicinska, W., VanHooke, J., DeLuca, H. F. and Yamada, S. (2000) Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain. Proc. Natl. Acad. Sci. U.S.A. 97, 1467-1472. https://doi.org/10.1073/pnas.020522697

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