{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T03:52:52Z","timestamp":1781927572503,"version":"3.54.5"},"reference-count":40,"publisher":"Pharmaceutical Society of Japan","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biological &amp; Pharmaceutical Bulletin","Biol. Pharm. Bull."],"published-print":{"date-parts":[[2026,6,19]]},"DOI":"10.1248\/bpb.b26-00155","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:10:16Z","timestamp":1781820616000},"page":"974-982","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of the Ligand-Dependent Coactivator Recruitment of the Nuclear Receptor Pregnane X Receptor Using Its Three-Alanine Residues-Inserted Mutant"],"prefix":"10.1248","volume":"49","author":[{"given":"Ayaka","family":"Sugawara","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52\u20131 Yada, Suruga-ku, Shizuoka 422\u20138526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Shizu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52\u20131 Yada, Suruga-ku, Shizuoka 422\u20138526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Nishiguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52\u20131 Yada, Suruga-ku, Shizuoka 422\u20138526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotona","family":"Motokatsu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52\u20131 Yada, Suruga-ku, Shizuoka 422\u20138526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuomi","family":"Hosaka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52\u20131 Yada, Suruga-ku, Shizuoka 422\u20138526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takamitsu","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52\u20131 Yada, Suruga-ku, Shizuoka 422\u20138526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouichi","family":"Yoshinari","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52\u20131 Yada, Suruga-ku, Shizuoka 422\u20138526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"163","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"1) Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. <i>Proc. Natl. Acad. Sci. U.S.A.<\/i>, <b>95<\/b>, 12208\u201312213 (1998).","DOI":"10.1073\/pnas.95.21.12208"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2) Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. <i>J. Clin. Invest.<\/i>, <b>102<\/b>, 1016\u20131023 (1998).","DOI":"10.1172\/JCI3703"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3) Tolson AH, Wang H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. <i>Adv. Drug Deliv. Rev.<\/i>, <b>62<\/b>, 1238\u20131249 (2010).","DOI":"10.1016\/j.addr.2010.08.006"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4) Handschin C, Meyer UA. Induction of drug metabolism: the role of nuclear receptors. <i>Pharmacol. Rev.<\/i>, <b>55<\/b>, 649\u2013673 (2003).","DOI":"10.1124\/pr.55.4.2"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5) Willson TM, Kliewer SA. PXR, CAR and drug metabolism. <i>Nat. Rev. Drug Discov.<\/i>, <b>1<\/b>, 259\u2013266 (2002).","DOI":"10.1038\/nrd753"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6) Yan J, Xie W. A brief history of the discovery of PXR and CAR as xenobiotic receptors. <i>Acta Pharm. Sin. B<\/i>, <b>6<\/b>, 450\u2013452 (2016).","DOI":"10.1016\/j.apsb.2016.06.011"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7) Konno Y, Negishi M, Kodama S. The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. <i>Drug Metab. Pharmacokinet.<\/i>, <b>23<\/b>, 8\u201313 (2008).","DOI":"10.2133\/dmpk.23.8"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8) Hakkola J, Rysa J, Hukkanen J. Regulation of hepatic energy metabolism by the nuclear receptor PXR. <i>Biochim. Biophys. Acta. Gene Regul. Mech.<\/i>, <b>1859<\/b>, 1072\u20131082 (2016).","DOI":"10.1016\/j.bbagrm.2016.03.012"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9) Yoshinari K, Shizu R. Distinct roles of the sister nuclear receptors PXR and CAR in liver cancer development. <i>Drug Metab. Dispos.<\/i>, <b>50<\/b>, 1019\u20131026 (2022).","DOI":"10.1124\/dmd.121.000481"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10) Oladimeji PO, Chen T. PXR: more than just a master xenobiotic receptor. <i>Mol. Pharmacol.<\/i>, <b>93<\/b>, 119\u2013127 (2018).","DOI":"10.1124\/mol.117.110155"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11) Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. <i>Steroids<\/i>, <b>72<\/b>, 231\u2013246 (2007).","DOI":"10.1016\/j.steroids.2006.12.006"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12) de Lera AR, Bourguet W, Altucci L, Gronemeyer H. Design of selective nuclear receptor modulators: RAR and RXR as a case study. <i>Nat. Rev. Drug Discov.<\/i>, <b>6<\/b>, 811\u2013820 (2007).","DOI":"10.1038\/nrd2398"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13) Nagy L, Schwabe JW. Mechanism of the nuclear receptor molecular switch. <i>Trends Biochem. Sci.<\/i>, <b>29<\/b>, 317\u2013324 (2004).","DOI":"10.1016\/j.tibs.2004.04.006"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14) Rigalli JP, Theile D, Nilles J, Weiss J. Regulation of PXR function by coactivator and corepressor proteins: ligand binding is just the beginning. <i>Cells<\/i>, <b>10<\/b>, 3137 (2021).","DOI":"10.3390\/cells10113137"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15) Masuyama H, Suwaki N, Tateishi Y, Nakatsukasa H, Segawa T, Hiramatsu Y. The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. <i>Mol. Endocrinol.<\/i>, <b>19<\/b>, 1170\u20131180 (2005).","DOI":"10.1210\/me.2004-0434"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16) Nemetchek MD, Chrisman IM, Rayl ML, Voss AH, Hughes TS. A structural mechanism of nuclear receptor biased agonism. <i>Proc. Natl. Acad. Sci. U.S.A.<\/i>, <b>119<\/b>, e2215333119 (2022).","DOI":"10.1073\/pnas.2215333119"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17) Burgermeister E, Schnoebelen A, Flament A, Benz J, Stihle M, Gsell B, Rufer A, Ruf A, Kuhn B, M\u00e4rki HP, Mizrahi J, Sebokova E, Niesor E, Meyer M. A novel partial agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) recruits PPARgamma-coactivator-1alpha, prevents triglyceride accumulation, and potentiates insulin signaling <i>in vitro<\/i>. <i>Mol. Endocrinol.<\/i>, <b>20<\/b>, 809\u2013830 (2006).","DOI":"10.1210\/me.2005-0171"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18) Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte <i>versus<\/i> osteoblast differentiation. <i>Endocrinology<\/i>, <b>143<\/b>, 2376\u20132384 (2002).","DOI":"10.1210\/endo.143.6.8834"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19) Squires EJ, Sueyoshi T, Negishi M. Cytoplasmic localization of pregnane X receptor and ligand-dependent nuclear translocation in mouse liver. <i>J. Biol. Chem.<\/i>, <b>279<\/b>, 49307\u201349314 (2004).","DOI":"10.1074\/jbc.M407281200"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20) Saradhi M, Sengupta A, Mukhopadhyay G, Tyagi RK. Pregnane and Xenobiotic Receptor (PXR\/SXR) resides predominantly in the nuclear compartment of the interphase cell and associates with the condensed chromosomes during mitosis. <i>Biochim. Biophys. Acta Mol. Cell Res.<\/i>, <b>1746<\/b>, 85\u201394 (2005).","DOI":"10.1016\/j.bbamcr.2005.10.004"},{"key":"21","doi-asserted-by":"crossref","unstructured":"21) Shizu R, Nishiguchi H, Tashiro S, Sato T, Sugawara A, Kanno Y, Hosaka T, Sasaki T, Yoshinari K. Helix 12 stabilization contributes to basal transcriptional activity of PXR. <i>J. Biol. Chem.<\/i>, <b>297<\/b>, 100978 (2021).","DOI":"10.1016\/j.jbc.2021.100978"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22) Shizu R, Otsuka Y, Ezaki K, Ishii C, Arakawa S, Amaike Y, Abe T, Hosaka T, Sasaki T, Kanno Y, Miyata M, Yamazoe Y, Yoshinari K. Antiepileptic drug-activated constitutive androstane receptor inhibits peroxisome proliferator-activated receptor alpha and peroxisome proliferator-activated receptor gamma coactivator 1alpha-dependent gene expression to increase blood triglyceride levels. <i>Mol. Pharmacol.<\/i>, <b>98<\/b>, 634\u2013647 (2020).","DOI":"10.1124\/molpharm.120.000103"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23) Okamura M, Shizu R, Hosaka T, Sasaki T, Yoshinari K. Possible involvement of the competition for the transcriptional coactivator glucocorticoid receptor-interacting protein 1 in the inflammatory signal-dependent suppression of PXR-mediated CYP3A induction <i>in vitro<\/i>. <i>Drug Metab. Pharmacokinet.<\/i>, <b>34<\/b>, 272\u2013279 (2019).","DOI":"10.1016\/j.dmpk.2019.04.005"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24) Shizu R, Ezaki K, Sato T, Sugawara A, Hosaka T, Sasaki T, Yoshinari K. PXR Suppresses PPARalpha-dependent HMGCS2 gene transcription by inhibiting the interaction between PPARalpha and PGC1alpha. <i>Cells<\/i>, <b>10<\/b>, 3550 (2021).","DOI":"10.3390\/cells10123550"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25) Rastinejad F, Huang P, Chandra V, Khorasanizadeh S. Understanding nuclear receptor form and function using structural biology. <i>J. Mol. Endocrinol.<\/i>, <b>51<\/b>, T1\u2013T21 (2013).","DOI":"10.1530\/JME-13-0173"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26) Batista MR, Mart\u00ednez L. Dynamics of nuclear receptor Helix-12 switch of transcription activation by modeling time-resolved fluorescence anisotropy decays. <i>Biophys. J.<\/i>, <b>105<\/b>, 1670\u20131680 (2013).","DOI":"10.1016\/j.bpj.2013.07.032"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27) Dawson MI, Xia Z. The retinoid X receptors and their ligands. <i>Biochim. Biophys. Acta Mol. Cell Biol. Lipids<\/i>, <b>1821<\/b>, 21\u201356 (2012).","DOI":"10.1016\/j.bbalip.2011.09.014"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28) Brust R, Shang J, Fuhrmann J, Mosure SA, Bass J, Cano A, Heidari Z, Chrisman IM, Nemetchek MD, Blayo A-L, Griffin PR, Kamenecka TM, Hughes TS, Kojetin DJ. A structural mechanism for directing corepressor-selective inverse agonism of PPAR\u03b3. <i>Nat. Commun.<\/i>, <b>9<\/b>, 4687 (2018).","DOI":"10.1038\/s41467-018-07133-w"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29) Huber AD, Wright WC, Lin W, Majumder K, Low JA, Wu J, Buchman CD, Pintel DJ, Chen T. Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning. <i>Cell. Mol. Life Sci.<\/i>, <b>78<\/b>, 317\u2013335 (2021).","DOI":"10.1007\/s00018-020-03505-y"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30) Iguchi Y, Yamashita Y, Gohda K, Fujimori K, Sera Y, Imanaka T, Yamaguchi M, Une M, Teno N. FLG249 exhibits FXR antagonist activity by inducing dissociation of both corepressors and coactivators from FXR. <i>Biol. Pharm. Bull.<\/i>, <b>48<\/b>, 1016\u20131021 (2025).","DOI":"10.1248\/bpb.b25-00095"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31) Mitsutani M, Yokoyama M, Hano H, Morita A, Matsushita M, Tagami T, Moriyama K. Resmetirom is an effective thyromimetics for the chemical rescue of thyroid hormone receptor mutants. <i>Biol. Pharm. Bull.<\/i>, <b>48<\/b>, 463\u2013474 (2025).","DOI":"10.1248\/bpb.b24-00845"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32) Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. <i>Nature<\/i>, <b>387<\/b>, 733\u2013736 (1997).","DOI":"10.1038\/42750"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33) Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG. The transcriptional co-activator p\/CIP binds CBP and mediates nuclear-receptor function. <i>Nature<\/i>, <b>387<\/b>, 677\u2013684 (1997).","DOI":"10.1038\/42652"},{"key":"34","unstructured":"34) Guillien M, le Maire A, Mouhand A, Bernad\u00f3 P, Bourguet W, Ban\u00e8res J-L, Sibille N. Chapter Three\u2014IDPs and their complexes in GPCR and nuclear receptor signaling. <i>Prog. Mol. Biol. Transl. Sci.<\/i>, <b>174<\/b>, 105\u2013155 (2020)."},{"key":"35","doi-asserted-by":"crossref","unstructured":"35) Pike ACW, Brzozowski AM, Walton J, Hubbard RE, Thorsell A-G, Li Y-L, Gustafsson J-\u00c5., Carlquist M. Structural insights into the mode of action of a pure antiestrogen. <i>Structure<\/i>, <b>9<\/b>, 145\u2013153 (2001).","DOI":"10.1016\/S0969-2126(01)00568-8"},{"key":"36","doi-asserted-by":"crossref","unstructured":"36) Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, Lundasen T, Hughes T, Kojetin DJ. Nuclear receptors and their selective pharmacologic modulators. <i>Pharmacol. Rev.<\/i>, <b>65<\/b>, 710\u2013778 (2013).","DOI":"10.1124\/pr.112.006833"},{"key":"37","doi-asserted-by":"crossref","unstructured":"37) Hall JM, McDonnell DP, Korach KS. Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements. <i>Mol. Endocrinol.<\/i>, <b>16<\/b>, 469\u2013486 (2002).","DOI":"10.1210\/mend.16.3.0814"},{"key":"38","doi-asserted-by":"crossref","unstructured":"38) Smith CL, O\u2019Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. <i>Endocr. Rev.<\/i>, <b>25<\/b>, 45\u201371 (2004).","DOI":"10.1210\/er.2003-0023"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39) Issa LL, Leong GM, Barry JB, Sutherland RL, Eisman JA. Glucocorticoid receptor-interacting protein-1 and receptor-associated coactivator-3 differentially interact with the vitamin D receptor (VDR) and regulate VDR-retinoid X receptor transcriptional cross-talk. <i>Endocrinology<\/i>, <b>142<\/b>, 1606\u20131615 (2001).","DOI":"10.1210\/endo.142.4.8068"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40) Toriyabe T, Nagata K, Takada T, Aratsu Y, Matsubara T, Yoshinari K, Yamazoe Y. Unveiling a new essential <i>cis<\/i> element for the transactivation of the CYP3A4 gene by xenobiotics. <i>Mol. Pharmacol.<\/i>, <b>75<\/b>, 677\u2013684 (2009).","DOI":"10.1124\/mol.108.050575"}],"container-title":["Biological and Pharmaceutical Bulletin"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/bpb\/49\/6\/49_b26-00155\/_pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T03:39:26Z","timestamp":1781926766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/bpb\/49\/6\/49_b26-00155\/_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,19]]},"references-count":40,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1248\/bpb.b26-00155","relation":{},"ISSN":["0918-6158","1347-5215"],"issn-type":[{"value":"0918-6158","type":"print"},{"value":"1347-5215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,19]]},"article-number":"b26-00155"}}