{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T17:53:24Z","timestamp":1791136404133,"version":"4.1.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"7542","license":[{"start":{"date-parts":[[2014,12,22]],"date-time":"2014-12-22T00:00:00Z","timestamp":1419206400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2015,3]]},"DOI":"10.1038\/nature14035","type":"journal-article","created":{"date-parts":[[2014,12,19]],"date-time":"2014-12-19T04:47:37Z","timestamp":1418964457000},"page":"247-250","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":202,"title":["Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant"],"prefix":"10.1038","volume":"519","author":[{"given":"Jie","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Mobarec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kolb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M.","family":"Rosenbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,12,22]]},"reference":[{"key":"BFnature14035_CR1","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1111\/bph.12415","volume":"171","author":"J Li","year":"2014","unstructured":"Li, J., Hu, Z. & de Lecea, L. The hypocretins\/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171, 332\u2013350 (2014)","journal-title":"Br. J. Pharmacol."},{"key":"BFnature14035_CR2","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/S1474-4422(14)70053-5","volume":"13","author":"D Michelson","year":"2014","unstructured":"Michelson, D. et al. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol. 13, 461\u2013471 (2014)","journal-title":"Lancet Neurol."},{"key":"BFnature14035_CR3","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1124\/mol.63.6.1256","volume":"63","author":"R Fredriksson","year":"2003","unstructured":"Fredriksson, R., Lagerstr\u00f6m, M. C., Lundin, L.-G. & Schi\u00f6th, H. B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63, 1256\u20131272 (2003)","journal-title":"Mol. Pharmacol."},{"key":"BFnature14035_CR4","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/bph.12261","volume":"171","author":"CJ Winrow","year":"2014","unstructured":"Winrow, C. J. & Renger, J. J. Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br. J. Pharmacol. 171, 283\u2013293 (2014)","journal-title":"Br. J. Pharmacol."},{"key":"BFnature14035_CR5","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1254\/jphs.92.259","volume":"92","author":"Y Zhu","year":"2003","unstructured":"Zhu, Y. et al. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J. Pharmacol. Sci. 92, 259\u2013266 (2003)","journal-title":"J. Pharmacol. Sci."},{"key":"BFnature14035_CR6","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/S0092-8674(00)81965-0","volume":"98","author":"L Lin","year":"1999","unstructured":"Lin, L. et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365\u2013376 (1999)","journal-title":"Cell"},{"key":"BFnature14035_CR7","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/S0092-8674(00)81973-X","volume":"98","author":"RM Chemelli","year":"1999","unstructured":"Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437\u2013451 (1999)","journal-title":"Cell"},{"key":"BFnature14035_CR8","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/S0140-6736(99)05582-8","volume":"355","author":"S Nishino","year":"2000","unstructured":"Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39\u201340 (2000)","journal-title":"Lancet"},{"key":"BFnature14035_CR9","doi-asserted-by":"publisher","first-page":"5320","DOI":"10.1021\/jm100541c","volume":"53","author":"CD Cox","year":"2010","unstructured":"Cox, C. D. et al. Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J. Med. Chem. 53, 5320\u20135332 (2010)","journal-title":"J. Med. Chem."},{"key":"BFnature14035_CR10","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1126\/science.1150609","volume":"318","author":"DM Rosenbaum","year":"2007","unstructured":"Rosenbaum, D. M. et al. GPCR engineering yields high-resolution structural insights into 2-adrenergic receptor function. Science 318, 1266\u20131273 (2007)","journal-title":"Science"},{"key":"BFnature14035_CR11","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nature07101","volume":"454","author":"T Warne","year":"2008","unstructured":"Warne, T. et al. Structure of a \u03b21-adrenergic G-protein-coupled receptor. Nature 454, 486\u2013491 (2008)","journal-title":"Nature"},{"key":"BFnature14035_CR12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev.biophys.050708.133655","volume":"38","author":"M Caffrey","year":"2009","unstructured":"Caffrey, M. Crystallizing membrane proteins for structure determination: use of lipidic mesophases. Annu. Rev. Biophys. 38, 29\u201351 (2009)","journal-title":"Annu. Rev. Biophys."},{"key":"BFnature14035_CR13","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/nature11558","volume":"490","author":"JF White","year":"2012","unstructured":"White, J. F. et al. Structure of the agonist-bound neurotensin receptor. Nature 490, 508\u2013513 (2012)","journal-title":"Nature"},{"key":"BFnature14035_CR14","doi-asserted-by":"publisher","first-page":"E655","DOI":"10.1073\/pnas.1317903111","volume":"111","author":"P Egloff","year":"2014","unstructured":"Egloff, P. et al. Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli. Proc. Natl Acad. Sci. USA 111, E655\u2013E662 (2014)","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFnature14035_CR15","doi-asserted-by":"publisher","first-page":"2923","DOI":"10.1074\/jbc.M507394200","volume":"281","author":"C Horcajada","year":"2006","unstructured":"Horcajada, C., Guinovart, J. J., Fita, I. & Ferrer, J. C. Crystal structure of an archaeal glycogen synthase: insights into oligomerization and substrate binding of eukaryotic glycogen synthases. J. Biol. Chem. 281, 2923\u20132931 (2006)","journal-title":"J. Biol. Chem."},{"key":"BFnature14035_CR16","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature10954","volume":"485","author":"A Manglik","year":"2012","unstructured":"Manglik, A. et al. Crystal structure of the \u00b5-opioid receptor bound to a morphinan antagonist. Nature 485, 321\u2013326 (2012)","journal-title":"Nature"},{"key":"BFnature14035_CR17","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1126\/science.1194396","volume":"330","author":"B Wu","year":"2010","unstructured":"Wu, B. et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066\u20131071 (2010)","journal-title":"Science"},{"key":"BFnature14035_CR18","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1124\/mol.110.064584","volume":"78","author":"P Malherbe","year":"2010","unstructured":"Malherbe, P. et al. Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA). Mol. Pharmacol. 78, 81\u201393 (2010)","journal-title":"Mol. Pharmacol."},{"key":"BFnature14035_CR19","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/nature10867","volume":"482","author":"AC Kruse","year":"2012","unstructured":"Kruse, A. C. et al. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482, 552\u2013556 (2012)","journal-title":"Nature"},{"key":"BFnature14035_CR20","doi-asserted-by":"publisher","first-page":"29171","DOI":"10.1074\/jbc.M103747200","volume":"276","author":"JA Ballesteros","year":"2001","unstructured":"Ballesteros, J. A. Activation of the \u03b22-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6. J. Biol. Chem. 276, 29171\u201329177 (2001)","journal-title":"J. Biol. Chem."},{"key":"BFnature14035_CR21","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nature08650","volume":"463","author":"MP Bokoch","year":"2010","unstructured":"Bokoch, M. P. et al. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 463, 108\u2013112 (2010)","journal-title":"Nature"},{"key":"BFnature14035_CR22","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nature09648","volume":"469","author":"SGF Rasmussen","year":"2011","unstructured":"Rasmussen, S. G. F. et al. Structure of a nanobody-stabilized active state of the \u03b22 adrenoceptor. Nature 469, 175\u2013180 (2011)","journal-title":"Nature"},{"key":"BFnature14035_CR23","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nature12735","volume":"504","author":"AC Kruse","year":"2013","unstructured":"Kruse, A. C. et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504, 101\u2013106 (2013)","journal-title":"Nature"},{"key":"BFnature14035_CR24","doi-asserted-by":"publisher","first-page":"2997","DOI":"10.1016\/j.bmcl.2009.04.026","volume":"19","author":"CD Cox","year":"2009","unstructured":"Cox, C. D. et al. Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding. Bioorg. Med. Chem. Lett. 19, 2997\u20133001 (2009)","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"BFnature14035_CR25","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/S0092-8674(00)80949-6","volume":"92","author":"T Sakurai","year":"1998","unstructured":"Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573\u2013585 (1998)","journal-title":"Cell"},{"key":"BFnature14035_CR26","doi-asserted-by":"publisher","first-page":"6843","DOI":"10.1073\/pnas.0812657106","volume":"106","author":"P Kolb","year":"2009","unstructured":"Kolb, P. et al. Structure-based discovery of \u03b22-adrenergic receptor ligands. Proc. Natl Acad. Sci. USA 106, 6843\u20136848 (2009)","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFnature14035_CR27","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/nm1544","volume":"13","author":"C Brisbare-Roch","year":"2007","unstructured":"Brisbare-Roch, C. et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nature Med. 13, 150\u2013155 (2007)","journal-title":"Nature Med."},{"key":"BFnature14035_CR28","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1111\/j.1476-5381.2009.00127.x","volume":"156","author":"P Malherbe","year":"2009","unstructured":"Malherbe, P. et al. Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX2 receptor. Br. J. Pharmacol. 156, 1326\u20131341 (2009)","journal-title":"Br. J. Pharmacol."},{"key":"BFnature14035_CR29","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/sj.bjp.0705610","volume":"141","author":"CJ Langmead","year":"2004","unstructured":"Langmead, C. J. et al. Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br. J. Pharmacol. 141, 340\u2013346 (2004)","journal-title":"Br. J. Pharmacol."},{"key":"BFnature14035_CR30","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.ejphar.2011.05.074","volume":"667","author":"D-T Tran","year":"2011","unstructured":"Tran, D.-T. et al. Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists. Eur. J. Pharmacol. 667, 120\u2013128 (2011)","journal-title":"Eur. J. Pharmacol."},{"key":"BFnature14035_CR31","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1006\/abio.1995.1533","volume":"231","author":"BK Kobilka","year":"1995","unstructured":"Kobilka, B. K. Amino and carboxyl terminal modifications to facilitate the production and purification of a G protein-coupled receptor. Anal. Biochem. 231, 269\u2013271 (1995)","journal-title":"Anal. Biochem."},{"key":"BFnature14035_CR32","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/nprot.2009.31","volume":"4","author":"M Caffrey","year":"2009","unstructured":"Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nature Protocols 4, 706\u2013731 (2009)","journal-title":"Nature Protocols"},{"key":"BFnature14035_CR33","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","volume":"276","author":"Z Otwinowski","year":"1997","unstructured":"Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307\u2013326 (1997)","journal-title":"Methods Enzymol."},{"key":"BFnature14035_CR34","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","volume":"40","author":"AJ McCoy","year":"2007","unstructured":"McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658\u2013674 (2007)","journal-title":"J. Appl. Crystallogr."},{"key":"BFnature14035_CR35","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S0907444909052925","volume":"66","author":"PD Adams","year":"2010","unstructured":"Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213\u2013221 (2010)","journal-title":"Acta Crystallogr. D"},{"key":"BFnature14035_CR36","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1107\/S0907444907033938","volume":"64","author":"K Cowtan","year":"2008","unstructured":"Cowtan, K. Fitting molecular fragments into electron density. Acta Crystallogr. D 64, 83\u201389 (2008)","journal-title":"Acta Crystallogr. D"},{"key":"BFnature14035_CR37","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","volume":"66","author":"P Emsley","year":"2010","unstructured":"Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486\u2013501 (2010)","journal-title":"Acta Crystallogr. D"},{"key":"BFnature14035_CR38","first-page":"109-\u2013111","volume":"29","author":"J Painter","year":"2006","unstructured":"Painter, J. & Merritt, E. A. TLSMD web server for the generation of multi-group TLS models. J. Appl. Crystallogr. 29, 109-\u2013111 (2006)","journal-title":"J. Appl. Crystallogr."},{"key":"BFnature14035_CR39","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1107\/S0907444904011679","volume":"60","author":"AW Sch\u00fcttelkopf","year":"2004","unstructured":"Sch\u00fcttelkopf, A. W. & van Aalten, D. M. F. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D 60, 1355\u20131363 (2004)","journal-title":"Acta Crystallogr. D"},{"key":"BFnature14035_CR40","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","volume":"66","author":"VB Chen","year":"2010","unstructured":"Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12\u201321 (2010)","journal-title":"Acta Crystallogr. D"},{"key":"BFnature14035_CR41","doi-asserted-by":"publisher","first-page":"6507","DOI":"10.1021\/jp010454y","volume":"105","author":"W Rocchia","year":"2001","unstructured":"Rocchia, W., Alexov, E. & Honig, B. Extending the applicability of the nonlinear Poisson\u2013Boltzmann equation: multiple dielectric constants and multivalent ions. J. Phys. Chem. B 105, 6507\u20136514 (2001)","journal-title":"J. Phys. Chem. B"},{"key":"BFnature14035_CR42","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1093\/protein\/8.2.127","volume":"8","author":"AC Wallace","year":"1995","unstructured":"Wallace, A. C., Laskowski, R. A. & Thornton, J. M. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 8, 127\u2013134 (1995)","journal-title":"Protein Eng."},{"key":"BFnature14035_CR43","doi-asserted-by":"publisher","first-page":"5712","DOI":"10.1021\/jm9006966","volume":"52","author":"JJ Irwin","year":"2009","unstructured":"Irwin, J. J. et al. Automated docking screens: a feasibility study. J. Med. Chem. 52, 5712\u20135720 (2009)","journal-title":"J. Med. Chem."},{"key":"BFnature14035_CR44","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1021\/ci100214a","volume":"50","author":"MM Mysinger","year":"2010","unstructured":"Mysinger, M. M. & Shoichet, B. K. Rapid context-dependent ligand desolvation in molecular docking. J. Chem. Inf. Model. 50, 1561\u20131573 (2010)","journal-title":"J. Chem. Inf. Model."},{"key":"BFnature14035_CR45","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","volume":"30","author":"GM Morris","year":"2009","unstructured":"Morris, G. M. et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785\u20132791 (2009)","journal-title":"J. Comput. Chem."},{"key":"BFnature14035_CR46","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1021\/ci060084g","volume":"46","author":"J Kirchmair","year":"2006","unstructured":"Kirchmair, J., Wolber, G., Laggner, C. & Langer, T. Comparative performance assessment of the conformational model generators Omega and Catalyst: a large-scale survey on the retrieval of protein-bound ligand conformations. J. Chem. Inf. Model. 46, 1848\u20131861 (2006)","journal-title":"J. Chem. Inf. Model."},{"key":"BFnature14035_CR47","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.1021\/ci200274q","volume":"51","author":"G Neudert","year":"2011","unstructured":"Neudert, G. & Klebe, G. DSX: a knowledge-based scoring function for the assessment of protein-ligand complexes. J. Chem. Inf. Model. 51, 2731\u20132745 (2011)","journal-title":"J. Chem. Inf. Model."}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/nature14035.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/nature14035","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/nature14035.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T14:27:37Z","timestamp":1684420057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/nature14035"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,22]]},"references-count":47,"journal-issue":{"issue":"7542","published-print":{"date-parts":[[2015,3]]}},"alternative-id":["BFnature14035"],"URL":"https:\/\/doi.org\/10.1038\/nature14035","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725287892.793504492","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.725287892.793502770","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.725287892.793503903","asserted-by":"object"}]},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,22]]},"assertion":[{"value":"16 September 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2014","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2014","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}