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Probing a water channel near the A-ring of receptor-bound 1 alpha,25-dihydroxyvitamin D3 with selected 2 alpha-substituted analogues.

Hourai S, Fujishima T, Kittaka A, Suhara Y, Takayama H, Rochel N, Moras D
J Med Chem 49 5199-205 (2006)
Related entries: 2har, 2has, 2hb7, 2hb8

Cited: 43 times
EuropePMC logo PMID: 16913708

Abstract

The crystal structure of the vitamin D receptor (VDR) in complex with 1 alpha,25(OH)2D3 revealed the presence of several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, we report the crystal structures of the human VDR ligand binding domain bound to selected C-2 alpha substituted analogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacements do not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, all analogues affect the presence and/or the location of the above water molecules. The integrity of the channel interactions and specific C-2 alpha analogue directed additional interactions correlate with the binding affinity of the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 cell differentiation. Our overall findings highlight a rational approach to the design of more potent ligands by building in features revealed in the crystal structures.

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  2. 1α,25(OH)2-3-epi-vitamin D3, a natural physiological metabolite of vitamin D3: its synthesis, biological activity and crystal structure with its receptor. Molnár F, Sigüeiro R, Sato Y, Araujo C, Schuster I, Antony P, Peluso J, Muller C, Mouriño A, Moras D, Rochel N. PLoS One 6 e18124 (2011)
  3. Gaining ligand selectivity in thyroid hormone receptors via entropy. Martínez L, Nascimento AS, Nunes FM, Phillips K, Aparicio R, Dias SM, Figueira AC, Lin JH, Nguyen P, Apriletti JW, Neves FA, Baxter JD, Webb P, Skaf MS, Polikarpov I. Proc Natl Acad Sci U S A 106 20717-20722 (2009)
  4. The vitamin D analog, MART-10, represses metastasis potential via downregulation of epithelial-mesenchymal transition in pancreatic cancer cells. Chiang KC, Yeh CN, Hsu JT, Jan YY, Chen LW, Kuo SF, Takano M, Kittaka A, Chen TC, Chen WT, Pang JH, Yeh TS, Juang HH. Cancer Lett 354 235-244 (2014)
  5. Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo. Chiang KC, Yeh CN, Hsu JT, Yeh TS, Jan YY, Wu CT, Chen HY, Jwo SC, Takano M, Kittaka A, Juang HH, Chen TC. Cell Cycle 12 1316-1325 (2013)
  6. Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations. Peräkylä M. Eur Biophys J 38 185-198 (2009)
  7. Crystal structures of complexes of vitamin D receptor ligand-binding domain with lithocholic acid derivatives. Masuno H, Ikura T, Morizono D, Orita I, Yamada S, Shimizu M, Ito N. J Lipid Res 54 2206-2213 (2013)
  8. MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase. Chiang KC, Yeh CN, Hsu JT, Chen LW, Kuo SF, Sun CC, Huang CC, Pang JH, Flanagan JN, Takano M, Kittaka A, Juang HH, Yang SW, Chen TC. J Steroid Biochem Mol Biol 138 427-434 (2013)
  9. MART-10, a New Generation of Vitamin D Analog, Is More Potent than 1α,25-Dihydroxyvitamin D(3) in Inhibiting Cell Proliferation and Inducing Apoptosis in ER+ MCF-7 Breast Cancer Cells. Chiang KC, Yeh CN, Chen SC, Shen SC, Hsu JT, Yeh TS, Pang JH, Su LJ, Takano M, Kittaka A, Juang HH, Chen TC. Evid Based Complement Alternat Med 2012 310872 (2012)
  10. Structure-based design of a superagonist ligand for the vitamin D nuclear receptor. Hourai S, Rodrigues LC, Antony P, Reina-San-Martin B, Ciesielski F, Magnier BC, Schoonjans K, Mouriño A, Rochel N, Moras D. Chem Biol 15 383-392 (2008)
  11. 2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation, and crystal structure. Shimizu M, Miyamoto Y, Takaku H, Matsuo M, Nakabayashi M, Masuno H, Udagawa N, DeLuca HF, Ikura T, Ito N. Bioorg Med Chem 16 6949-6964 (2008)
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  13. Novel vitamin d analogs for prostate cancer therapy. Chen TC, Kittaka A. ISRN Urol 2011 301490 (2011)
  14. 2-Methylene 19-nor-25-dehydro-1alpha-hydroxyvitamin D3 26,23-lactones: synthesis, biological activities and molecular basis of passive antagonism. Yoshimoto N, Inaba Y, Yamada S, Makishima M, Shimizu M, Yamamoto K. Bioorg Med Chem 16 457-473 (2008)
  15. Synthesis of 2α-heteroarylalkyl active vitamin d3 with therapeutic effect on enhancing bone mineral density in vivo. Matsuo M, Hasegawa A, Takano M, Saito H, Kakuda S, Chida T, Takagi K, Ochiai E, Horie K, Harada Y, Takimoto-Kamimura M, Takenouchi K, Sawada D, Kittaka A. ACS Med Chem Lett 4 671-674 (2013)
  16. Synthesis of 2alpha-propoxy-1alpha,25-dihydroxyvitamin D3 and comparison of its metabolism by human CYP24A1 and rat CYP24A1. Saito N, Suhara Y, Abe D, Kusudo T, Ohta M, Yasuda K, Sakaki T, Honzawa S, Fujishima T, Kittaka A. Bioorg Med Chem 17 4296-4301 (2009)
  17. Creative synthesis of novel vitamin D analogs for health and disease. Kittaka A, Saito N, Honzawa S, Takenouchi K, Ishizuka S, Chen TC, Peleg S, Kato S, Arai MA. J Steroid Biochem Mol Biol 103 269-276 (2007)
  18. MART-10, a newly synthesized vitamin D analog, represses metastatic potential of head and neck squamous carcinoma cells. Yang SW, Tsai CY, Pan YC, Yeh CN, Pang JH, Takano M, Kittaka A, Juang HH, Chen TC, Chiang KC. Drug Des Devel Ther 10 1995-2002 (2016)
  19. A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy. Kashiwagi H, Ono Y, Ohta M, Itoh S, Ichikawa F, Harada S, Takeda S, Sekiguchi N, Ishigai M, Takahashi T. Bioorg Med Chem 21 1823-1833 (2013)
  20. Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 position. Saitoh H, Chida T, Takagi K, Horie K, Sawai Y, Nakamura Y, Harada Y, Takenouchi K, Kittaka A. Org Biomol Chem 9 3954-3964 (2011)
  21. Agonist and antagonist binding to the nuclear vitamin D receptor: dynamics, mutation effects and functional implications. Yaghmaei S, Roberts C, Ai R, Mizwicki MT, Chang CE. In Silico Pharmacol 1 2 (2013)
  22. Confirmation of high-throughput screening data and novel mechanistic insights into VDR-xenobiotic interactions by orthogonal assays. Mahapatra D, Franzosa JA, Roell K, Kuenemann MA, Houck KA, Reif DM, Fourches D, Kullman SW. Sci Rep 8 8883 (2018)
  23. Design and synthesis of novel 1,25-dihydroxyvitamin D3 analogues having a spiro-oxetane fused at the C2 position in the A-ring. Fujishima T, Nozaki T, Suenaga T. Bioorg Med Chem 21 5209-5217 (2013)
  24. Nonsteroidal ecdysone receptor agonists use a water channel for binding to the ecdysone receptor complex EcR/USP. Browning C, McEwen AG, Mori K, Yokoi T, Moras D, Nakagawa Y, Billas IML. J Pestic Sci 46 88-100 (2021)
  25. A human vitamin D receptor mutant activated by cholecalciferol. Ousley AM, Castillo HS, Duraj-Thatte A, Doyle DF, Azizi B. J Steroid Biochem Mol Biol 125 202-210 (2011)
  26. Effects of 2-substitution on 14-epi-19-nortachysterol-mediated biological events: based on synthesis and X-ray co-crystallographic analysis with the human vitamin D receptor. Sawada D, Kakuda S, Takeuchi A, Kawagoe F, Takimoto-Kamimura M, Kittaka A. Org Biomol Chem 16 2448-2455 (2018)
  27. Synthesis of 2alpha-substituted-14-epi-previtamin D3 and its genomic activity. Sawada D, Katayama T, Tsukuda Y, Saito N, Takano M, Saito H, Takagi K, Ochiai E, Ishizuka S, Takenouchi K, Kittaka A. Bioorg Med Chem Lett 19 5397-5400 (2009)


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