{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T19:32:37Z","timestamp":1791660757387,"version":"4.3.4"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T00:00:00Z","timestamp":1720742400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T00:00:00Z","timestamp":1720742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the G<jats:sub>q<\/jats:sub> and G<jats:sub>i<\/jats:sub> heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming \u03b2-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2\/3 and the G\u03b1 subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1\u2019s versatility in G protein coupling.<\/jats:p>","DOI":"10.1038\/s41422-024-00997-2","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T09:02:26Z","timestamp":1720774946000},"page":"725-734","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Structural basis of tethered agonism and G protein coupling of protease-activated receptors"],"prefix":"10.1038","volume":"34","author":[{"given":"Jia","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Li","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimeng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erli","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2314-4800","authenticated-orcid":false,"given":"Xin","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5349-8592","authenticated-orcid":false,"given":"Chunyou","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6829-8144","authenticated-orcid":false,"given":"H. Eric","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-0244","authenticated-orcid":false,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,12]]},"reference":[{"key":"997_CR1","doi-asserted-by":"publisher","first-page":"16041","DOI":"10.1016\/S0021-9258(17)33970-4","volume":"269","author":"J Chen","year":"1994","unstructured":"Chen, J., Ishii, M., Wang, L., Ishii, K. & Coughlin, S. R. Thrombin receptor activation. Confirmation of the intramolecular tethered liganding hypothesis and discovery of an alternative intermolecular liganding mode. J. Biol. Chem. 269, 16041\u201316045 (1994).","journal-title":"J. Biol. Chem."},{"key":"997_CR2","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1016\/0092-8674(91)90261-V","volume":"64","author":"T-KH Vu","year":"1991","unstructured":"Vu, T.-K. H., Hung, D. T., Wheaton, V. I. & Coughlin, S. R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64, 1057\u20131068 (1991).","journal-title":"Cell"},{"key":"997_CR3","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/35025229","volume":"407","author":"SR Coughlin","year":"2000","unstructured":"Coughlin, S. R. Thrombin signalling and protease-activated receptors. Nature 407, 258\u2013264 (2000).","journal-title":"Nature"},{"key":"997_CR4","doi-asserted-by":"publisher","first-page":"6642","DOI":"10.1073\/pnas.95.12.6642","volume":"95","author":"WF Xu","year":"1998","unstructured":"Xu, W. F. et al. Cloning and characterization of human protease-activated receptor 4. Proc. Natl. Acad. Sci. USA 95, 6642\u20136646 (1998).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"997_CR5","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1038\/386502a0","volume":"386","author":"H Ishihara","year":"1997","unstructured":"Ishihara, H. et al. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 386, 502\u2013506 (1997).","journal-title":"Nature"},{"key":"997_CR6","doi-asserted-by":"publisher","first-page":"9208","DOI":"10.1073\/pnas.91.20.9208","volume":"91","author":"S Nystedt","year":"1994","unstructured":"Nystedt, S., Emilsson, K., Wahlestedt, C. & Sundelin, J. Molecular cloning of a potential proteinase activated receptor. Proc. Natl. Acad. Sci. USA 91, 9208\u20139212 (1994).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"997_CR7","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1161\/CIRCULATIONAHA.105.574830","volume":"114","author":"AJ Leger","year":"2006","unstructured":"Leger, A. J., Covic, L. & Kuliopulos, A. Protease-activated receptors in cardiovascular diseases. Circulation 114, 1070\u20131077 (2006).","journal-title":"Circulation"},{"key":"997_CR8","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1111\/j.1538-7836.2005.01377.x","volume":"3","author":"SR Coughlin","year":"2005","unstructured":"Coughlin, S. R. Protease\u2010activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800\u20131814 (2005).","journal-title":"J. Thromb. Haemost."},{"key":"997_CR9","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1182\/blood-2015-11-636472","volume":"128","author":"MT Nieman","year":"2016","unstructured":"Nieman, M. T. Protease-activated receptors in hemostasis. Blood 128, 169\u2013177 (2016).","journal-title":"Blood"},{"key":"997_CR10","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/nature11701","volume":"492","author":"C Zhang","year":"2012","unstructured":"Zhang, C. et al. High-resolution crystal structure of human protease-activated receptor 1. Nature 492, 387\u2013392 (2012).","journal-title":"Nature"},{"key":"997_CR11","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/368648a0","volume":"368","author":"RE Gerszten","year":"1994","unstructured":"Gerszten, R. E. et al. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface. Nature 368, 648\u2013651 (1994).","journal-title":"Nature"},{"key":"997_CR12","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1074\/jbc.272.4.2223","volume":"272","author":"AJ Barr","year":"1997","unstructured":"Barr, A. J., Brass, L. F. & Manning, D. R. Reconstitution of receptors and GTP-binding regulatory proteins (G proteins) in Sf9 cells. A direct evaluation of selectivity in receptor.G protein coupling. J. Biol. Chem. 272, 2223\u20132229 (1997).","journal-title":"J. Biol. Chem."},{"key":"997_CR13","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1073\/pnas.91.2.504","volume":"91","author":"S Offermanns","year":"1994","unstructured":"Offermanns, S., Laugwitz, K. L., Spicher, K. & Schultz, G. G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets. Proc. Natl. Acad. Sci. USA 91, 504\u2013508 (1994).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"997_CR14","doi-asserted-by":"publisher","first-page":"20831","DOI":"10.1016\/S0021-9258(19)36762-6","volume":"267","author":"DT Hung","year":"1992","unstructured":"Hung, D. T., Wong, Y. H., Vu, T. K. & Coughlin, S. R. The cloned platelet thrombin receptor couples to at least two distinct effectors to stimulate phosphoinositide hydrolysis and inhibit adenylyl cyclase. J. Biol. Chem. 267, 20831\u201320834 (1992).","journal-title":"J. Biol. Chem."},{"key":"997_CR15","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1083\/jcb.144.4.745","volume":"144","author":"B Klages","year":"1999","unstructured":"Klages, B., Brandt, U., Simon, M. I., Schultz, G. & Offermanns, S. Activation of G12\/G13 results in shape change and Rho\/Rho-kinase-mediated myosin light chain phosphorylation in mouse platelets. J. Cell Biol. 144, 745\u2013754 (1999).","journal-title":"J. Cell Biol."},{"key":"997_CR16","doi-asserted-by":"crossref","unstructured":"Offermanns, S., Toombs, C. F., Hu, Y.-H. & Simon, M. I. Defective platelet activation in G\u03b1q-deficient mice. Nature 389, 183\u2013186 (1997).","DOI":"10.1038\/38284"},{"key":"997_CR17","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1016\/S0021-9258(17)42110-7","volume":"269","author":"S Winitz","year":"1994","unstructured":"Winitz, S. et al. Expression of a mutant Gi2 alpha subunit inhibits ATP and thrombin stimulation of cytoplasmic phospholipase A2-mediated arachidonic acid release independent of Ca2+ and mitogen-activated protein kinase regulation. J. Biol. Chem. 269, 1889\u20131895 (1994).","journal-title":"J. Biol. Chem."},{"key":"997_CR18","doi-asserted-by":"publisher","first-page":"373","DOI":"10.2217\/fca-2019-0090","volume":"16","author":"US Tantry","year":"2020","unstructured":"Tantry, U. S. et al. Vorapaxar in the treatment of cardiovascular diseases. Future Cardiol. 16, 373\u2013384 (2020).","journal-title":"Future Cardiol."},{"key":"997_CR19","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s00228-011-1120-6","volume":"68","author":"T Kosoglou","year":"2012","unstructured":"Kosoglou, T. et al. Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects. Eur. J. Clin. Pharmacol. 68, 249\u2013258 (2012).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"997_CR20","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1056\/NEJMoa1200933","volume":"366","author":"DA Morrow","year":"2012","unstructured":"Morrow, D. A. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404\u20131413 (2012).","journal-title":"N. Engl. J. Med."},{"key":"997_CR21","doi-asserted-by":"publisher","first-page":"5884","DOI":"10.1021\/jm0502236","volume":"48","author":"S Chackalamannil","year":"2005","unstructured":"Chackalamannil, S. et al. Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents. J. Med. Chem. 48, 5884\u20135887 (2005).","journal-title":"J. Med. Chem."},{"key":"997_CR22","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.tibs.2018.04.003","volume":"43","author":"M Chaturvedi","year":"2018","unstructured":"Chaturvedi, M. et al. Emerging paradigm of intracellular targeting of G protein-coupled receptors. Trends Biochem. Sci. 43, 533\u2013546 (2018).","journal-title":"Trends Biochem. Sci."},{"key":"997_CR23","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1097\/FJC.0000000000001236","volume":"80","author":"H Xu","year":"2022","unstructured":"Xu, H. & Tilley, D. G. Pepducin-mediated G protein-coupled receptor signaling in the cardiovascular system. J. Cardiovasc. Pharmacol. 80, 378\u2013385 (2022).","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"997_CR24","first-page":"2675","volume":"141","author":"G K\u00fcnze","year":"2023","unstructured":"K\u00fcnze, G. & Isermann, B. Targeting biased signaling by PAR1: function and molecular mechanism of parmodulins. Blood 141, 2675\u20132684 (2023).","journal-title":"Blood"},{"key":"997_CR25","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/978-1-0716-1752-6_21","volume":"2383","author":"E Michael","year":"2022","unstructured":"Michael, E., Covic, L. & Kuliopulos, A. Lipopeptide pepducins as therapeutic agents. Methods Mol. Biol. 2383, 307\u2013333 (2022).","journal-title":"Methods Mol. Biol."},{"key":"997_CR26","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nature22309","volume":"545","author":"RKY Cheng","year":"2017","unstructured":"Cheng, R. K. Y. et al. Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545, 112\u2013115 (2017).","journal-title":"Nature"},{"key":"997_CR27","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1038\/s41594-021-00645-y","volume":"28","author":"Y-L Yin","year":"2021","unstructured":"Yin, Y.-L. et al. Molecular basis for kinin selectivity and activation of the human bradykinin receptors. Nat. Struct. Mol. Biol. 28, 755\u2013761 (2021).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"997_CR28","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1038\/aps.2016.69","volume":"37","author":"P Liu","year":"2016","unstructured":"Liu, P. et al. The structural basis of the dominant negative phenotype of the G\u03b1i1\u03b21\u03b32 G203A\/A326S heterotrimer. Acta Pharmacol. Sin. 37, 1259\u20131272 (2016).","journal-title":"Acta Pharmacol. Sin."},{"key":"997_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17933-8","volume":"11","author":"J Duan","year":"2020","unstructured":"Duan, J. et al. Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy. Nat. Commun. 11, 4121 (2020).","journal-title":"Nat. Commun."},{"key":"997_CR30","doi-asserted-by":"publisher","first-page":"3414","DOI":"10.1111\/bph.15489","volume":"178","author":"Y Seo","year":"2021","unstructured":"Seo, Y. et al. Novel positive allosteric modulator of protease-activated receptor 1 promotes skin wound healing in hairless mice. Br. J. Pharmacol. 178, 3414\u20133427 (2021).","journal-title":"Br. J. Pharmacol."},{"key":"997_CR31","doi-asserted-by":"publisher","first-page":"10631","DOI":"10.3390\/ijms231810631","volume":"23","author":"Y Heo","year":"2022","unstructured":"Heo, Y. et al. GB83, an agonist of PAR2 with a unique mechanism of action distinct from Trypsin and PAR2-AP. Int. J. Mol. Sci. 23, 10631 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"997_CR32","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.mce.2016.11.023","volume":"449","author":"MJ Woolley","year":"2017","unstructured":"Woolley, M. J. & Conner, A. C. Understanding the common themes and diverse roles of the second extracellular loop (ECL2) of the GPCR super-family. Mol. Cell. Endocrinol. 449, 3\u201311 (2017).","journal-title":"Mol. Cell. Endocrinol."},{"key":"997_CR33","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/j.chembiol.2003.10.014","volume":"10","author":"S Seeley","year":"2003","unstructured":"Seeley, S. et al. Structural basis for thrombin activation of a protease-activated receptor: inhibition of intramolecular liganding. Chem. Biol. 10, 1033\u20131041 (2003).","journal-title":"Chem. Biol."},{"key":"997_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33173-4","volume":"13","author":"X Zhu","year":"2022","unstructured":"Zhu, X. et al. Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling. Nat. Commun. 13, 5513 (2022).","journal-title":"Nat. Commun."},{"key":"997_CR35","doi-asserted-by":"publisher","first-page":"4340","DOI":"10.1016\/j.molcel.2022.10.009","volume":"82","author":"Y Qian","year":"2022","unstructured":"Qian, Y. et al. Structural insights into adhesion GPCR ADGRL3 activation and Gq, Gs, Gi, and G12 coupling. Mol. Cell 82, 4340\u20134352.e6 (2022).","journal-title":"Mol. Cell"},{"key":"997_CR36","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1038\/s41586-022-04580-w","volume":"604","author":"X Qu","year":"2022","unstructured":"Qu, X. et al. Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1. Nature 604, 779\u2013785 (2022).","journal-title":"Nature"},{"key":"997_CR37","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/s41586-022-04590-8","volume":"604","author":"P Xiao","year":"2022","unstructured":"Xiao, P. et al. Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. Nature 604, 771\u2013778 (2022).","journal-title":"Nature"},{"key":"997_CR38","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1038\/s41586-022-04619-y","volume":"604","author":"Y-Q Ping","year":"2022","unstructured":"Ping, Y.-Q. et al. Structural basis for the tethered peptide activation of adhesion GPCRs. Nature 604, 763\u2013770 (2022).","journal-title":"Nature"},{"key":"997_CR39","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/s41586-022-04575-7","volume":"604","author":"X Barros-\u00c1lvarez","year":"2022","unstructured":"Barros-\u00c1lvarez, X. et al. The tethered peptide activation mechanism of adhesion GPCRs. Nature 604, 757\u2013762 (2022).","journal-title":"Nature"},{"key":"997_CR40","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.50279","volume":"8","author":"Q Zhou","year":"2019","unstructured":"Zhou, Q. et al. Common activation mechanism of class A GPCRs. Elife 8, e50279 (2019).","journal-title":"Elife"},{"key":"997_CR41","doi-asserted-by":"publisher","first-page":"5628","DOI":"10.1021\/acs.biochem.7b00747","volume":"56","author":"A Manglik","year":"2017","unstructured":"Manglik, A. & Kruse, A. C. Structural basis for G protein-coupled receptor activation. Biochemistry 56, 5628\u20135634 (2017).","journal-title":"Biochemistry"},{"key":"997_CR42","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1038\/s41594-021-00674-7","volume":"28","author":"AS Hauser","year":"2021","unstructured":"Hauser, A. S. et al. GPCR activation mechanisms across classes and macro\/microscales. Nat. Struct. Mol. Biol. 28, 879\u2013888 (2021).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"997_CR43","doi-asserted-by":"publisher","first-page":"15785","DOI":"10.1074\/jbc.M115.636316","volume":"290","author":"P Zhang","year":"2015","unstructured":"Zhang, P. et al. Allosteric activation of a G protein-coupled receptor with cell-penetrating receptor mimetics. J. Biol. Chem. 290, 15785\u201315798 (2015).","journal-title":"J. Biol. Chem."},{"key":"997_CR44","doi-asserted-by":"publisher","first-page":"4109","DOI":"10.1074\/jbc.M509525200","volume":"281","author":"S Swift","year":"2006","unstructured":"Swift, S. et al. Role of the PAR1 receptor 8th helix in signaling. J. Biol. Chem. 281, 4109\u20134116 (2006).","journal-title":"J. Biol. Chem."},{"key":"997_CR45","doi-asserted-by":"publisher","first-page":"5458","DOI":"10.1021\/bi9927078","volume":"39","author":"L Covic","year":"2000","unstructured":"Covic, L., Gresser, A. L. & Kuliopulos, A. Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 39, 5458\u20135467 (2000).","journal-title":"Biochemistry"},{"key":"997_CR46","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/nature14287","volume":"520","author":"D Zhang","year":"2015","unstructured":"Zhang, D. et al. Two disparate ligand-binding sites in the human P2Y1 receptor. Nature 520, 317\u2013321 (2015).","journal-title":"Nature"},{"key":"997_CR47","first-page":"382","volume":"14","author":"B Li","year":"2023","unstructured":"Li, B. et al. Structural insights into signal transduction of the purinergic receptors P2Y1R and P2Y12R. Protein Cell 14, 382\u2013386 (2023).","journal-title":"Protein Cell"},{"key":"997_CR48","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1038\/s41589-021-00841-3","volume":"17","author":"Q Liu","year":"2021","unstructured":"Liu, Q. et al. Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor. Nat. Chem. Biol. 17, 1238\u20131244 (2021).","journal-title":"Nat. Chem. Biol."},{"key":"997_CR49","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41421-022-00420-3","volume":"8","author":"Y Ding","year":"2022","unstructured":"Ding, Y. et al. Structural insights into human brain\u2013gut peptide cholecystokinin receptors. Cell Discov. 8, 55 (2022).","journal-title":"Cell Discov."},{"key":"997_CR50","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/nature10361","volume":"477","author":"SGF Rasmussen","year":"2011","unstructured":"Rasmussen, S. G. F. et al. Crystal structure of the \u03b22 adrenergic receptor\u2013Gs protein complex. Nature 477, 549\u2013555 (2011).","journal-title":"Nature"},{"key":"997_CR51","doi-asserted-by":"publisher","first-page":"22273","DOI":"10.1016\/S0021-9258(18)41524-4","volume":"268","author":"O Moro","year":"1993","unstructured":"Moro, O., Lameh, J., H\u00f6gger, P. & Sad\u00e9e, W. Hydrophobic amino acid in the i2 loop plays a key role in receptor-G protein coupling. J. Biol. Chem. 268, 22273\u201322276 (1993).","journal-title":"J. Biol. Chem."},{"key":"997_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29072-3","volume":"13","author":"J Duan","year":"2022","unstructured":"Duan, J. et al. Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors. Nat. Commun. 13, 1364 (2022).","journal-title":"Nat. Commun."},{"key":"997_CR53","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1126\/science.aaz5346","volume":"367","author":"A Qiao","year":"2020","unstructured":"Qiao, A. et al. Structural basis of Gs and Gi recognition by the human glucagon receptor. Science 367, 1346\u20131352 (2020).","journal-title":"Science"},{"key":"997_CR54","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1111\/j.1476-5381.2010.01006.x","volume":"161","author":"X Chen","year":"2010","unstructured":"Chen, X. et al. Structural determinants in the second intracellular loop of the human cannabinoid CB1 receptor mediate selective coupling to Gs and Gi. Br. J. Pharmacol. 161, 1817\u20131834 (2010).","journal-title":"Br. J. Pharmacol."},{"key":"997_CR55","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.cell.2018.11.040","volume":"176","author":"K Krishna Kumar","year":"2019","unstructured":"Krishna Kumar, K. et al. Structure of a signaling cannabinoid receptor 1-G protein complex. Cell 176, 448\u2013458.e12 (2019).","journal-title":"Cell"},{"key":"997_CR56","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/s41589-022-01130-3","volume":"19","author":"S Chen","year":"2023","unstructured":"Chen, S., Teng, X. & Zheng, S. Molecular basis for the selective G protein signaling of somatostatin receptors. Nat. Chem. Biol. 19, 133\u2013140 (2023).","journal-title":"Nat. Chem. Biol."},{"key":"997_CR57","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/s41422-022-00669-z","volume":"32","author":"L-N Chen","year":"2022","unstructured":"Chen, L.-N. et al. Structures of the endogenous peptide- and selective non-peptide agonist-bound SSTR2 signaling complexes. Cell Res. 32, 785\u2013788 (2022).","journal-title":"Cell Res."},{"key":"997_CR58","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1182\/blood-2015-01-623835","volume":"125","author":"MT Nieman","year":"2015","unstructured":"Nieman, M. T. PARtitioning protease signaling. Blood 125, 1853\u20131855 (2015).","journal-title":"Blood"},{"key":"997_CR59","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1182\/blood-2014-09-599910","volume":"125","author":"O Aisiku","year":"2015","unstructured":"Aisiku, O. et al. Parmodulins inhibit thrombus formation without inducing endothelial injury caused by vorapaxar. Blood 125, 1976\u20131985 (2015).","journal-title":"Blood"},{"key":"997_CR60","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1167\/iovs.14-14831","volume":"56","author":"SS Twining","year":"2015","unstructured":"Twining, S. S., Warejcka, D., Andreae, E. & Conklyn, D. Protease activated receptor 1 (PAR1) plays a role in corneal wound healing. Invest. Ophthalmol. Vis. Sci. 56, 738 (2015).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"997_CR61","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12959-019-0194-8","volume":"17","author":"DM Heuberger","year":"2019","unstructured":"Heuberger, D. M. & Schuepbach, R. A. Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb. J. 17, 4 (2019).","journal-title":"Thromb. J."},{"key":"997_CR62","doi-asserted-by":"publisher","first-page":"5375","DOI":"10.1016\/j.cell.2023.10.019","volume":"186","author":"L Deng","year":"2023","unstructured":"Deng, L. et al. S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis. Cell 186, 5375\u20135393.e25 (2023).","journal-title":"Cell"},{"key":"997_CR63","doi-asserted-by":"publisher","first-page":"32010","DOI":"10.18632\/oncotarget.25880","volume":"9","author":"C Tekin","year":"2018","unstructured":"Tekin, C. et al. PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer. Oncotarget 9, 32010\u201332023 (2018).","journal-title":"Oncotarget"},{"key":"997_CR64","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.cell.2004.12.018","volume":"120","author":"A Boire","year":"2005","unstructured":"Boire, A. et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303\u2013313 (2005).","journal-title":"Cell"},{"key":"997_CR65","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/nmeth.4193","volume":"14","author":"SQ Zheng","year":"2017","unstructured":"Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331\u2013332 (2017).","journal-title":"Nat. Methods"},{"key":"997_CR66","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.jsb.2015.08.008","volume":"192","author":"A Rohou","year":"2015","unstructured":"Rohou, A. & Grigorieff, N. CTFFIND4: Fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216 (2015).","journal-title":"J. Struct. Biol."},{"key":"997_CR67","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.42166","volume":"7","author":"J Zivanov","year":"2018","unstructured":"Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. Elife 7, e42166 (2018).","journal-title":"Elife"},{"key":"997_CR68","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/nmeth.2727","volume":"11","author":"A Kucukelbir","year":"2014","unstructured":"Kucukelbir, A., Sigworth, F. J. & Tagare, H. D. Quantifying the local resolution of cryo-EM density maps. Nat. Methods 11, 63\u201365 (2014).","journal-title":"Nat. Methods"},{"key":"997_CR69","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.1016\/j.cell.2020.08.024","volume":"182","author":"K Kim","year":"2020","unstructured":"Kim, K. et al. Structure of a hallucinogen-activated Gq-coupled 5-HT2A serotonin receptor. Cell 182, 1574\u20131588.e19 (2020).","journal-title":"Cell"},{"key":"997_CR70","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1107\/S0907444904019158","volume":"60","author":"P Emsley","year":"2004","unstructured":"Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126\u20132132 (2004).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"997_CR71","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1107\/S2059798318002425","volume":"74","author":"TI Croll","year":"2018","unstructured":"Croll, T. I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D Struct. Biol. 74, 519\u2013530 (2018).","journal-title":"Acta Crystallogr. D Struct. Biol."},{"key":"997_CR72","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1107\/S2059798319011471","volume":"75","author":"D Liebschner","year":"2019","unstructured":"Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. Sect. Struct. Biol. 75, 861\u2013877 (2019).","journal-title":"Acta Crystallogr. Sect. Struct. Biol."},{"key":"997_CR73","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 Biol. Crystallogr. 66, 12\u201321 (2010).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"997_CR74","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14728-9","volume":"11","author":"Y Zhuang","year":"2020","unstructured":"Zhuang, Y. et al. Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nat. Commun. 11, 885 (2020).","journal-title":"Nat. Commun."},{"key":"997_CR75","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"P Ef","year":"2004","unstructured":"Ef, P. et al. UCSF Chimera\u2013a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605\u20131612 (2004).","journal-title":"J. Comput. Chem."},{"key":"997_CR76","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","volume":"30","author":"EF Pettersen","year":"2021","unstructured":"Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70\u201382 (2021).","journal-title":"Protein Sci."},{"key":"997_CR77","unstructured":"The PyMOL molecular graphics system, version 2.0 (Schr\u00f6dinger, LLC, 2015)."},{"key":"997_CR78","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-27975-9","volume":"13","author":"J Qin","year":"2022","unstructured":"Qin, J. et al. Molecular mechanism of agonism and inverse agonism in ghrelin receptor. Nat. Commun. 13, 300 (2022).","journal-title":"Nat. Commun."}],"container-title":["Cell Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00997-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00997-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00997-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T22:53:17Z","timestamp":1727736797000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41422-024-00997-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,12]]},"references-count":78,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["997"],"URL":"https:\/\/doi.org\/10.1038\/s41422-024-00997-2","relation":{},"ISSN":["1748-7838"],"issn-type":[{"value":"1748-7838","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,12]]},"assertion":[{"value":"27 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}