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Identification of key amino acid residues in the hTGR5–nomilin interaction and construction of its binding model

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  • Takashi Sasaki
  • Moeko Mita
  • Naho Ikari
  • Ayane Kuboyama
  • Shuzo Hashimoto
  • Tatsuya Kaneko
  • Masaji Ishiguro
  • Makoto Shimizu
  • Jun Inoue
  • Ryuichiro Sato

Abstract

TGR5, a member of the G protein-coupled receptor (GPCR) family, is activated by bile acids. Because TGR5 promotes energy expenditure and improves glucose homeostasis, it is recognized as a key target in treating metabolic diseases. We previously showed that nomilin, a citrus limonoid, activates TGR5 and confers anti-obesity and anti-hyperglycemic effects in mice. Information on the TGR5–nomilin interaction regarding molecular structure, however, has not been reported. In the present study, we found that human TGR5 (hTGR5) shows higher nomilin responsiveness than does mouse TGR5 (mTGR5). Using mouse–human chimeric TGR5, we also found that three amino acid residues (Q77ECL1, R80ECL1, and Y893.29) are important in the hTGR5–nomilin interaction. Based on these results, an hTGR5–nomilin binding model was constructed using in silico docking simulation, demonstrating that four hydrophilic hydrogen-bonding interactions occur between nomilin and hTGR5. The binding mode of hTGR5–nomilin is vastly different from those of other TGR5 agonists previously reported, suggesting that TGR5 forms various binding patterns depending on the type of agonist. Our study promotes a better understanding of the structure of TGR5, and it may be useful in developing and screening new TGR5 agonists.

Suggested Citation

  • Takashi Sasaki & Moeko Mita & Naho Ikari & Ayane Kuboyama & Shuzo Hashimoto & Tatsuya Kaneko & Masaji Ishiguro & Makoto Shimizu & Jun Inoue & Ryuichiro Sato, 2017. "Identification of key amino acid residues in the hTGR5–nomilin interaction and construction of its binding model," PLOS ONE, Public Library of Science, vol. 12(6), pages 1-15, June.
  • Handle: RePEc:plo:pone00:0179226
    DOI: 10.1371/journal.pone.0179226
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    References listed on IDEAS

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    1. Mitsuhiro Watanabe & Sander M. Houten & Chikage Mataki & Marcelo A. Christoffolete & Brian W. Kim & Hiroyuki Sato & Nadia Messaddeq & John W. Harney & Osamu Ezaki & Tatsuhiko Kodama & Kristina Schoonj, 2006. "Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation," Nature, Nature, vol. 439(7075), pages 484-489, January.
    2. Hui-Woog Choe & Yong Ju Kim & Jung Hee Park & Takefumi Morizumi & Emil F. Pai & Norbert Krauß & Klaus Peter Hofmann & Patrick Scheerer & Oliver P. Ernst, 2011. "Crystal structure of metarhodopsin II," Nature, Nature, vol. 471(7340), pages 651-655, March.
    3. Søren G. F. Rasmussen & Hee-Jung Choi & Juan Jose Fung & Els Pardon & Paola Casarosa & Pil Seok Chae & Brian T. DeVree & Daniel M. Rosenbaum & Foon Sun Thian & Tong Sun Kobilka & Andreas Schnapp & Ing, 2011. "Structure of a nanobody-stabilized active state of the β2 adrenoceptor," Nature, Nature, vol. 469(7329), pages 175-180, January.
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