{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T21:31:47Z","timestamp":1793223107451,"version":"4.5.0"},"reference-count":49,"publisher":"Elsevier BV","issue":"10","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["jbc.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Biological Chemistry"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1016\/j.jbc.2026.113437","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T15:30:18Z","timestamp":1786548618000},"page":"113437","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":1,"title":["Intracellular pocket and ICL2 motifs govern G-protein coupling bias in NK1 receptor (TACR1) and NK2 receptor (TACR2)"],"prefix":"10.1016","volume":"302","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2116-1626","authenticated-orcid":false,"given":"Jacob E.","family":"Petersen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6869-0136","authenticated-orcid":false,"given":"Artem","family":"Pavlovskyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1411-9080","authenticated-orcid":false,"given":"Jesper J.","family":"Madsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thue W.","family":"Schwartz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Frimurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1216-7521","authenticated-orcid":false,"given":"Ole H.","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jbc.2026.113437_bib1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1152\/physrev.00031.2013","article-title":"Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease","volume":"94","author":"Steinhoff","year":"2014","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.jbc.2026.113437_bib2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1474-8673.1993.tb00396.x","article-title":"Tachykinin receptors and tachykinin receptor antagonists","volume":"13","author":"Maggi","year":"1993","journal-title":"J. Auton. Pharmacol."},{"key":"10.1016\/j.jbc.2026.113437_bib3","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jtos.2022.06.007","article-title":"Modulating the tachykinin: role of substance P and neurokinin receptor expression in ocular surface disorders","volume":"25","author":"Singh","year":"2022","journal-title":"Ocul. Surf."},{"key":"10.1016\/j.jbc.2026.113437_bib4","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1139\/y95-121","article-title":"Tachykinin NK2 receptors further characterized in the lung with nonpeptide receptor antagonists","volume":"73","author":"Advenier","year":"1995","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"10.1016\/j.jbc.2026.113437_bib5","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/BF02245629","article-title":"The anxiolytic-like activity of GR159897, a non-peptide NK2 receptor antagonist, in rodent and primate models of anxiety","volume":"121","author":"Walsh","year":"1995","journal-title":"Psychopharmacology"},{"key":"10.1016\/j.jbc.2026.113437_bib6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41421-022-00437-8","article-title":"Structural insights into the activation of neurokinin 2 receptor by neurokinin A","volume":"8","author":"Sun","year":"2022","journal-title":"Cell Discov."},{"key":"10.1016\/j.jbc.2026.113437_bib7","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41421-023-00564-w","article-title":"Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists","volume":"9","author":"Sun","year":"2023","journal-title":"Cell Discov"},{"key":"10.1016\/j.jbc.2026.113437_bib8","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/all.12052","article-title":"Substance P antagonist improves both obesity and asthma in a mouse model","volume":"68","author":"Ramalho","year":"2013","journal-title":"Allergy"},{"key":"10.1016\/j.jbc.2026.113437_bib9","doi-asserted-by":"crossref","DOI":"10.1016\/j.lfs.2022.121078","article-title":"Neurokinin 3 receptor antagonist-induced adipocyte activation improves obesity and metabolism in PCOS-like mice","volume":"310","author":"Zhang","year":"2022","journal-title":"Life Sci."},{"key":"10.1016\/j.jbc.2026.113437_bib10","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1210\/en.2010-1345","article-title":"Substance P (SP)-Neurokinin-1 Receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action","volume":"152","author":"Karagiannides","year":"2011","journal-title":"Endocrinology"},{"key":"10.1016\/j.jbc.2026.113437_bib11","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1053\/j.gastro.2007.12.032","article-title":"Substance P as a novel anti-obesity target","volume":"134","author":"Karagiannides","year":"2008","journal-title":"Gastroenterology"},{"key":"10.1016\/j.jbc.2026.113437_bib12","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0012527","article-title":"The neurokinin 1 receptor antagonist, ezlopitant, reduces appetitive responding for sucrose and ethanol","volume":"5","author":"Steensland","year":"2010","journal-title":"PLoS ONE"},{"key":"10.1016\/j.jbc.2026.113437_bib13","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/s41586-024-08207-0","article-title":"NK2R control of energy expenditure and feeding to treat metabolic diseases","volume":"635","author":"Sass","year":"2024","journal-title":"Nature"},{"key":"10.1016\/j.jbc.2026.113437_bib14","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/s41594-026-01820-9","article-title":"Structurally defining neurokinin selectivity to improve NK2R agonists","volume":"33","author":"Pavlovskyi","year":"2026","journal-title":"Nat. Struct. Mol. Biol."},{"key":"10.1016\/j.jbc.2026.113437_bib15","first-page":"1","article-title":"Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography","volume":"10","author":"Chen","year":"2019","journal-title":"Nat. Commun."},{"key":"10.1016\/j.jbc.2026.113437_bib16","doi-asserted-by":"crossref","first-page":"13264","DOI":"10.1073\/pnas.1812717115","article-title":"Crystal structure of the human NK 1 tachykinin receptor","volume":"115","author":"Yin","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2026.113437_bib17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-07939-8","article-title":"Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists","volume":"10","author":"Sch\u00f6ppe","year":"2019","journal-title":"Nat. Commun."},{"key":"10.1016\/j.jbc.2026.113437_bib18","first-page":"1","article-title":"Modelling dynamics in protein crystal structures by ensemble refinement","volume":"2012","author":"Tom Burnley","year":"2012","journal-title":"eLife"},{"key":"10.1016\/j.jbc.2026.113437_bib19","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1016\/j.bpj.2019.03.024","article-title":"Allostery in coagulation factor VIIa revealed by ensemble refinement of crystallographic structures","volume":"116","author":"Sorensen","year":"2019","journal-title":"Biophys. J."},{"key":"10.1016\/j.jbc.2026.113437_bib20","doi-asserted-by":"crossref","DOI":"10.1002\/pro.4456","article-title":"Mechanistic basis of GPCR activation explored by ensemble refinement of crystallographic structures","volume":"31","author":"Madsen","year":"2022","journal-title":"Protein Sci."},{"key":"10.1016\/j.jbc.2026.113437_bib21","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2023.105438","article-title":"Deciphering specificity and cross-reactivity in tachykinin NK1 and NK2 receptors","volume":"299","author":"Madsen","year":"2023","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1126\/sciadv.abk2872","article-title":"Structures of neurokinin 1 receptor in complex with Gq and Gs proteins reveal substance P binding mode and unique activation features","volume":"7","author":"Thom","year":"2021","journal-title":"Sci. Adv."},{"key":"10.1016\/j.jbc.2026.113437_bib23","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41589-021-00890-8","article-title":"Selective G protein signaling driven by substance P\u2013neurokinin receptor dynamics","volume":"18","author":"Harris","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"10.1016\/j.jbc.2026.113437_bib24","doi-asserted-by":"crossref","first-page":"24495","DOI":"10.1074\/jbc.M115.641944","article-title":"Biased Gs versus Gq proteins and \u03b2-arrestin signaling in the NK1 receptor determined by interactions in the water hydrogen bond network","volume":"290","author":"Valentin-Hansen","year":"2015","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib25","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2024.107948","article-title":"Molecular determinants of neuropeptide-mediated activation mechanisms in tachykinin NK1 and NK2 receptors","volume":"300","author":"Petersen","year":"2024","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib26","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S1043-9471(05)80049-7","article-title":"Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors","volume":"25","author":"Ballesteros","year":"1995","journal-title":"Methods Neurosci."},{"key":"10.1016\/j.jbc.2026.113437_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.jbc.2025.108522","article-title":"Challenging activity and signaling bias in tachykinin NK1 and NK2 receptors by truncated neuropeptides","volume":"301","author":"Petersen","year":"2025","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib28","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.sbi.2017.04.010","article-title":"Active state structures of G protein-coupled receptors highlight the similarities and differences in the G protein and arrestin coupling interfaces","volume":"45","author":"Carpenter","year":"2017","journal-title":"Curr. Opin. Struct. Biol."},{"key":"10.1016\/j.jbc.2026.113437_bib29","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nature18966","article-title":"Structure of the adenosine A2A receptor bound to an engineered G protein","volume":"536","author":"Carpenter","year":"2016","journal-title":"Nature"},{"key":"10.1016\/j.jbc.2026.113437_bib30","doi-asserted-by":"crossref","DOI":"10.1016\/j.jsb.2025.108182","article-title":"Effects of G\u03b1 C-terminal deletion on the intrinsic GDP release\/GTPase activity and conformational dynamics","volume":"217","author":"Kim","year":"2025","journal-title":"J. Struct. Biol."},{"key":"10.1016\/j.jbc.2026.113437_bib31","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1038\/s41467-020-16975-2","article-title":"Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi\/o family","volume":"11","author":"Kim","year":"2020","journal-title":"Nat. Commun."},{"key":"10.1016\/j.jbc.2026.113437_bib32","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature10361","article-title":"Crystal structure of the \u03b22 adrenergic receptor\u2013Gs protein complex","volume":"477","author":"Rasmussen","year":"2011","journal-title":"Nature"},{"key":"10.1016\/j.jbc.2026.113437_bib33","doi-asserted-by":"crossref","first-page":"D335","DOI":"10.1093\/nar\/gkaa1080","article-title":"GPCRdb in 2021: integrating GPCR sequence, structure and function","volume":"49","author":"Kooistra","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.jbc.2026.113437_bib34","article-title":"Structural basis of peptide recognition and modulation for neuropeptide FF receptors","volume":"44","author":"Li","year":"2025","journal-title":"Cell Rep."},{"key":"10.1016\/j.jbc.2026.113437_bib35","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0167-4781(02)00546-8","article-title":"Molecular cloning and characterization of prokineticin receptors","volume":"1579","author":"Soga","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"10.1016\/j.jbc.2026.113437_bib36","doi-asserted-by":"crossref","first-page":"9435","DOI":"10.1074\/jbc.M209706200","article-title":"A G protein-coupled receptor responsive to bile acids","volume":"278","author":"Kawamata","year":"2003","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib37","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1038\/ncomms2968","article-title":"The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms","volume":"4","author":"M\u00fcller","year":"2013","journal-title":"Nat. Commun."},{"key":"10.1016\/j.jbc.2026.113437_bib38","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1016\/j.jmb.2013.04.011","article-title":"Conformational flexibility and structural dynamics in GPCR-mediated G protein activation: a perspective","volume":"425","author":"Preininger","year":"2013","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.jbc.2026.113437_bib39","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1515\/bmc.2010.022","article-title":"A fresh look at the Ramachandran plot and the occurrence of standard structures in proteins","volume":"1","author":"Hollingsworth","year":"2010","journal-title":"BMC"},{"key":"10.1016\/j.jbc.2026.113437_bib40","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/pro.3526","article-title":"Structural biology of G protein-coupled receptor signaling complexes","volume":"28","author":"Edward Zhou","year":"2019","journal-title":"Protein Sci."},{"key":"10.1016\/j.jbc.2026.113437_bib41","doi-asserted-by":"crossref","first-page":"11956","DOI":"10.1073\/pnas.1820944116","article-title":"Conformational plasticity of the intracellular cavity of GPCR\u2212G-protein complexes leads to G-protein promiscuity and selectivity","volume":"116","author":"Sandhu","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2026.113437_bib42","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: a web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib43","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1002\/jcc.23702","article-title":"CHARMM-GUI membrane builder toward realistic biological membrane simulations","volume":"35","author":"Wu","year":"2014","journal-title":"J. Comput. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib44","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1093\/nar\/gkr703","article-title":"OPM database and PPM web server: resources for positioning of proteins in membranes","volume":"40","author":"Lomize","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.jbc.2026.113437_bib45","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m: an improved force field for folded and intrinsically disordered proteins","volume":"14","author":"Huang","year":"2017","journal-title":"Nat. Methods"},{"key":"10.1016\/j.jbc.2026.113437_bib46","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: a new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"10.1016\/j.jbc.2026.113437_bib47","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: fast, flexible, and free","volume":"26","author":"Van Der Spoel","year":"2005","journal-title":"J. Comput. Chem."},{"key":"10.1016\/j.jbc.2026.113437_bib48","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: a 2D graphics environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"10.1016\/j.jbc.2026.113437_bib49","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1126\/science.1109237","article-title":"Transduction of receptor signals by \u00df-Arrestins","volume":"308","author":"Lefkowitz","year":"2005","journal-title":"Science"}],"container-title":["Journal of Biological Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925826023094?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925826023094?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T20:32:26Z","timestamp":1793219546000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0021925826023094"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":49,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["S0021925826023094"],"URL":"https:\/\/doi.org\/10.1016\/j.jbc.2026.113437","relation":{},"ISSN":["0021-9258"],"issn-type":[{"value":"0021-9258","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Intracellular pocket and ICL2 motifs govern G-protein coupling bias in NK1 receptor (TACR1) and NK2 receptor (TACR2)","name":"articletitle","label":"Article Title"},{"value":"Journal of Biological Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jbc.2026.113437","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.","name":"copyright","label":"Copyright"}],"article-number":"113437"}}