{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:45:38Z","timestamp":1791852338785,"version":"4.3.4"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"7877","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2021,9,23]]},"DOI":"10.1038\/s41586-021-03897-2","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T16:03:08Z","timestamp":1631116988000},"page":"571-576","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":154,"title":["Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia"],"prefix":"10.1038","volume":"597","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2055-7706","authenticated-orcid":false,"given":"Christopher J.","family":"Draper-Joyce","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Bhola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0162-212X","authenticated-orcid":false,"given":"Jinan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apurba","family":"Bhattarai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh T. N.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"India","family":"Cowie-Kent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1715-595X","authenticated-orcid":false,"given":"Kelly","family":"O\u2019Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling Yeong","family":"Chia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hariprasad","family":"Venugopal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Valant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0325-2524","authenticated-orcid":false,"given":"David M.","family":"Thal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Wootten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8782-0586","authenticated-orcid":false,"given":"Nicolas","family":"Panel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Carlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-609X","authenticated-orcid":false,"given":"Macdonald J.","family":"Christie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Scammells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren T.","family":"May","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-2473","authenticated-orcid":false,"given":"Patrick M.","family":"Sexton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6406-8993","authenticated-orcid":false,"given":"Radostin","family":"Danev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3714-1395","authenticated-orcid":false,"given":"Yinglong","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4146-965X","authenticated-orcid":false,"given":"Alisa","family":"Glukhova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7521-9969","authenticated-orcid":false,"given":"Wendy L.","family":"Imlach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4442-3294","authenticated-orcid":false,"given":"Arthur","family":"Christopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,8]]},"reference":[{"key":"3897_CR1","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1097\/00000542-199709000-00018","volume":"87","author":"I Nakamura","year":"1997","unstructured":"Nakamura, I., Ohta, Y. & Kemmotsu, O. M. Characterization of adenosine receptors mediating spinal sensory transmission related to nociceptive information in the rat. Anesthesiology 87, 577\u2013584 (1997).","journal-title":"Anesthesiology"},{"key":"3897_CR2","doi-asserted-by":"publisher","first-page":"235\u2013","DOI":"10.1016\/S0304-3959(97)00186-3","volume":"74","author":"A Poon","year":"1998","unstructured":"Poon, A. & Sawynok, J. Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. Pain 74, 235\u2013245 (1998).","journal-title":"Pain"},{"key":"3897_CR3","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.molmed.2010.12.006","volume":"17","author":"MJ Zylka","year":"2011","unstructured":"Zylka, M. J. Pain-relieving prospects for adenosine receptors and ectonucleotidases. Trends Mol. Med. 17, 188\u2013196 (2011).","journal-title":"Trends Mol. Med."},{"key":"3897_CR4","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1038\/d41586-019-02683-5","volume":"573","author":"A King","year":"2019","unstructured":"King, A. Analgesia without opioids. Nature 573, S4 (2019).","journal-title":"Nature"},{"key":"3897_CR5","doi-asserted-by":"publisher","first-page":"2448","DOI":"10.1001\/jama.2018.18472","volume":"320","author":"JW Busse","year":"2018","unstructured":"Busse, J. W. et al. Opioids for chronic noncancer pain: a systematic review and meta-analysis. JAMA 320, 2448\u20132460 (2018).","journal-title":"JAMA"},{"key":"3897_CR6","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/S0301-0082(02)00155-7","volume":"68","author":"JA Ribeiro","year":"2002","unstructured":"Ribeiro, J. A., Sebasti\u00e3o, A. M. & de Mendon\u00e7a, A. Adenosine receptors in the nervous system: pathophysiological implications. Prog. Neurobiol. 68, 377\u2013392 (2002).","journal-title":"Prog. Neurobiol."},{"key":"3897_CR7","first-page":"905","volume":"242","author":"JI Choca","year":"1987","unstructured":"Choca, J. I., Proudfit, H. K. & Green, R. D. Identification of A1 and A2 adenosine receptors in the rat spinal cord. J. Pharmacol. Exp. Ther. 242, 905\u2013910 (1987).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"3897_CR8","first-page":"757","volume":"247","author":"JI Choca","year":"1988","unstructured":"Choca, J. I., Green, R. D. & Proudfit, H. K. Adenosine A1 and A2 receptors of the substantia gelatinosa are located predominantly on intrinsic neurons: an autoradiography study. J. Pharmacol. Exp. Ther. 247, 757\u2013764 (1988).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"3897_CR9","doi-asserted-by":"publisher","first-page":"H949","DOI":"10.1152\/ajpheart.00741.2001","volume":"282","author":"Z Yang","year":"2002","unstructured":"Yang, Z. et al. Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction. Am. J. Physiol. Heart. Circ. Physiol. 282, H949\u2013H955 (2002).","journal-title":"Am. J. Physiol. Heart. Circ. Physiol."},{"key":"3897_CR10","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1124\/pr.54.2.323","volume":"54","author":"A Christopoulos","year":"2002","unstructured":"Christopoulos, A. & Kenakin, T. G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 54, 323\u2013374 (2002).","journal-title":"Pharmacol. Rev."},{"key":"3897_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1146\/annurev.pharmtox.47.120505.105159","volume":"47","author":"LT May","year":"2007","unstructured":"May, L. T. et al. Allosteric modulation of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 47, 1\u201351 (2007).","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"3897_CR12","first-page":"939","volume":"38","author":"RF Bruns","year":"1990","unstructured":"Bruns, R. F. & Fergus, J. H. Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes. Mol. Pharmacol. 38, 939\u2013949 (1990).","journal-title":"Mol. Pharmacol."},{"key":"3897_CR13","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0304-3959(02)00011-8","volume":"97","author":"X Li","year":"2002","unstructured":"Li, X. et al. Spinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain. Pain 97, 117\u2013125 (2002).","journal-title":"Pain"},{"key":"3897_CR14","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1111\/j.1471-4159.2005.03044.x","volume":"93","author":"SR Childers","year":"2005","unstructured":"Childers, S. R. et al. Allosteric modulation of adenosine A1 receptor coupling to G-proteins in brain. J. Neurochem. 93, 715\u2013723 (2005).","journal-title":"J. Neurochem."},{"key":"3897_CR15","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.neuropharm.2014.01.028","volume":"81","author":"F Vincenzi","year":"2014","unstructured":"Vincenzi, F. et al. TRR469, a potent A1 adenosine receptor allosteric modulator, exhibits anti-nociceptive properties in acute and neuropathic pain models in mice. Neuropharmacology 81, 6\u201314 (2014).","journal-title":"Neuropharmacology"},{"key":"3897_CR16","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1021\/tx500134g","volume":"27","author":"D Gramec","year":"2014","unstructured":"Gramec, D., Ma\u0161i\u010d, L. P. & Dolenc, M. S. Bioactivation potential of thiophene-containing drugs. Chem. Res. in Toxicol. 27, 1344\u20131358 (2014).","journal-title":"Chem. Res. in Toxicol."},{"key":"3897_CR17","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1124\/mol.116.105015","volume":"90","author":"AT Nguyen","year":"2016","unstructured":"Nguyen, A. T. et al. Role of the second extracellular loop of the adenosine A1 receptor on allosteric modulator binding, signaling, and cooperativity. Mol. Pharmacol. 90, 715\u2013725 (2016).","journal-title":"Mol. Pharmacol."},{"key":"3897_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-35266-x","volume":"8","author":"Y Miao","year":"2018","unstructured":"Miao, Y. et al. Structural basis for binding of allosteric drug leads in the adenosine A1 receptor. Sci. Rep. 8, 16836 (2018).","journal-title":"Sci. Rep."},{"key":"3897_CR19","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/j.cell.2017.01.042","volume":"168","author":"A Glukhova","year":"2017","unstructured":"Glukhova, A. et al. Structure of the adenosine A1 receptor reveals the basis for subtype selectivity. Cell 168, 867\u2013877 (2017).","journal-title":"Cell"},{"key":"3897_CR20","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41586-018-0259-z","volume":"559","author":"DM Thal","year":"2018","unstructured":"Thal, D. M. et al. Structural insights into G-protein-coupled receptor allostery. Nature 559, 45\u201353 (2018).","journal-title":"Nature"},{"key":"3897_CR21","doi-asserted-by":"publisher","first-page":"3584","DOI":"10.1021\/acs.jctc.5b00436","volume":"11","author":"Y Miao","year":"2015","unstructured":"Miao, Y., Feher, V. A. & McCammon, J. A. Gaussian accelerated molecular dynamics: unconstrained enhanced sampling and free energy calculation. J. Chem. Theory Comput. 11, 3584\u20133595 (2015).","journal-title":"J. Chem. Theory Comput."},{"key":"3897_CR22","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1124\/mol.115.099499","volume":"88","author":"WL Imlach","year":"2015","unstructured":"Imlach, W. L. et al. A positive allosteric modulator of the adenosine A1 receptor selectively inhibits primary afferent synaptic transmission in a neuropathic pain model. Mol. Pharmacol. 88, 460\u2013468 (2015).","journal-title":"Mol. Pharmacol."},{"key":"3897_CR23","doi-asserted-by":"publisher","first-page":"4543","DOI":"10.1021\/jm9002582","volume":"52","author":"L Aurelio","year":"2009","unstructured":"Aurelio, L. et al. Allosteric modulators of the adenosine A1 receptor: synthesis and pharmacological evaluation of 4-substituted 2-amino-3-benzoylthiophenes. J. Med. Chem. 52, 4543\u20134547 (2009).","journal-title":"J. Med. Chem."},{"key":"3897_CR24","doi-asserted-by":"publisher","first-page":"4614","DOI":"10.1073\/pnas.1320962111","volume":"111","author":"C Valant","year":"2014","unstructured":"Valant, C. et al. Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist. Proc. Natl Acad. Sci. USA 111, 4614\u20134619 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3897_CR25","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/S0306-4522(03)00480-9","volume":"121","author":"G Schulte","year":"2003","unstructured":"Schulte, G. et al. Distribution of antinociceptive adenosine A1 receptors in the spinal cord dorsal horn, and relationship to primary afferents and neuronal subpopulations. Neuroscience 121, 907\u2013916 (2003).","journal-title":"Neuroscience"},{"key":"3897_CR26","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3389\/fncir.2017.00055","volume":"11","author":"Z-Y Wu","year":"2017","unstructured":"Wu, Z.-Y. et al. Endomorphin-2 decreases excitatory synaptic transmission in the spinal ventral horn of the rat. Front. Neural Circuits 11, 55\u201355 (2017).","journal-title":"Front. Neural Circuits"},{"key":"3897_CR27","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.1523\/JNEUROSCI.04-09-02303.1984","volume":"4","author":"JG Geiger","year":"1984","unstructured":"Geiger, J. G., LaBella, F. S. & Nagy, J. I. Characterization and localization of adenosine receptors in rat spinal cord. J. Neurosci. 4, 2303\u20132310 (1984).","journal-title":"J. Neurosci."},{"key":"3897_CR28","doi-asserted-by":"publisher","first-page":"9407","DOI":"10.1073\/pnas.161292398","volume":"98","author":"B Johansson","year":"2001","unstructured":"Johansson, B. et al. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor. Proc. Natl Acad. Sci. USA 98, 9407\u20139412 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3897_CR29","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1021\/acsptsci.8b00017","volume":"1","author":"YL Liang","year":"2018","unstructured":"Liang, Y. L. et al. Dominant negative G proteins enhance formation and purification of agonist\u2013GPCR\u2013G protein complexes for structure determination. ACS Pharmacol. Transl. Sci. 1, 12\u201320 (2018).","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"3897_CR30","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/s41586-018-0236-6","volume":"558","author":"CJ Draper-Joyce","year":"2018","unstructured":"Draper-Joyce, C. J. et al. Structure of the adenosine-bound human adenosine A1 receptor\u2013Gi complex. Nature 558, 559\u2013563 (2018).","journal-title":"Nature"},{"key":"3897_CR31","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1038\/npp.2009.194","volume":"35","author":"K Leach","year":"2010","unstructured":"Leach, K. et al. Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties. Neuropsychopharmacology 35, 855\u2013869 (2010).","journal-title":"Neuropsychopharmacology"},{"key":"3897_CR32","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":"3897_CR33","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nature22309","volume":"545","author":"RK Cheng","year":"2017","unstructured":"Cheng, R. K. et al. Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545, 112\u2013115 (2017).","journal-title":"Nature"},{"key":"3897_CR34","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/nature25025","volume":"553","author":"N Robertson","year":"2018","unstructured":"Robertson, N. et al. Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727. Nature 553, 111\u2013114 (2018).","journal-title":"Nature"},{"key":"3897_CR35","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1038\/s41589-019-0387-2","volume":"15","author":"Z Shao","year":"2019","unstructured":"Shao, Z. et al. Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. Nat. Chem. Biol. 15, 1199\u20131205 (2019).","journal-title":"Nat. Chem. Biol."},{"key":"3897_CR36","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1038\/nsmb.3417","volume":"24","author":"J Lu","year":"2017","unstructured":"Lu, J. et al. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat. Struct. Mol. Biol. 24, 570\u2013577 (2017).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"3897_CR37","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1126\/science.aaw8981","volume":"364","author":"X Liu","year":"2019","unstructured":"Liu, X. et al. Mechanism of \u03b22AR regulation by an intracellular positive allosteric modulator. Science 364, 1283\u20131287 (2019).","journal-title":"Science"},{"key":"3897_CR38","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/s41422-021-00482-0","volume":"31","author":"Y Zhuang","year":"2021","unstructured":"Zhuang, Y. et al. Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor. Cell Res. 31, 593\u2013596 (2021).","journal-title":"Cell Res."},{"key":"3897_CR39","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nature18324","volume":"535","author":"BT DeVree","year":"2016","unstructured":"DeVree, B. T. et al. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature 535, 182\u2013186 (2016).","journal-title":"Nature"},{"key":"3897_CR40","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/0304-3959(90)91074-S","volume":"43","author":"Z Seltzer","year":"1990","unstructured":"Seltzer, Z., Dubner, R. & Shir, Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43, 205\u2013218 (1990).","journal-title":"Pain"},{"key":"3897_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/srep37104","volume":"6","author":"WL Imlach","year":"2016","unstructured":"Imlach, W. L. et al. Glycinergic dysfunction in a subpopulation of dorsal horn interneurons in a rat model of neuropathic pain. Sci. Rep.6, 37104 (2016).","journal-title":"Sci. Rep."},{"key":"3897_CR42","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1744-8069-10-26","volume":"10","author":"RP Bonin","year":"2014","unstructured":"Bonin, R. P., Bories, C. & De Koninck, Y. A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments. Mol. Pain 10, 10\u201326 (2014).","journal-title":"Mol. Pain"},{"key":"3897_CR43","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/0165-0270(95)00164-6","volume":"65","author":"RV St\u00f8rkson","year":"1996","unstructured":"St\u00f8rkson, R. V. et al. Lumbar catheterization of the spinal subarachnoid space in the rat. J. Neurosci. Methods 65, 167\u2013172 (1996).","journal-title":"J. Neurosci. Methods"},{"key":"3897_CR44","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1038\/nn.2407","volume":"12","author":"T King","year":"2009","unstructured":"King, T. et al. Unmasking the tonic-aversive state in neuropathic pain. Nat. Neurosci. 12, 1364\u20131366 (2009).","journal-title":"Nat. Neurosci."},{"key":"3897_CR45","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/nn.3881","volume":"18","author":"D Usoskin","year":"2015","unstructured":"Usoskin, D. et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat. Neurosci.18, 145\u2013153 (2015).","journal-title":"Nat. Neurosci."},{"key":"3897_CR46","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41592-019-0396-9","volume":"16","author":"M Schorb","year":"2019","unstructured":"Schorb, M. et al. Software tools for automated transmission electron microscopy. Nat. Methods 16, 471\u2013477 (2019).","journal-title":"Nat. Methods"},{"key":"3897_CR47","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":"3897_CR48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jsb.2015.11.003","volume":"193","author":"K Zhang","year":"2016","unstructured":"Zhang, K. Gctf: real-time CTF determination and correction. J. Struct. Biol.193, 1\u201312 (2016).","journal-title":"J. Struct. Biol."},{"key":"3897_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06002-w","volume":"9","author":"S Maeda","year":"2018","unstructured":"Maeda, S. et al. Development of an antibody fragment that stabilizes GPCR\/G-protein complexes. Nat. Commun. 9, 3712 (2018).","journal-title":"Nat. Commun."},{"key":"3897_CR50","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","volume":"66","author":"P Emsley","year":"2010","unstructured":"Emsley, P. et al. Features and development of Coot. Acta Crystallogr. D 66, 486\u2013501 (2010).","journal-title":"Acta Crystallogr. D"},{"key":"3897_CR51","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":"3897_CR52","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":"3897_CR53","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera\u2014a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605\u20131612 (2004).","journal-title":"J. Comput. Chem."},{"key":"3897_CR54","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.bcp.2015.11.013","volume":"99","author":"JA Baltos","year":"2016","unstructured":"Baltos, J. A. et al. Quantification of adenosine A1 receptor biased agonism: implications for drug discovery. Biochem. Pharmacol. 99, 101\u2013112 (2016).","journal-title":"Biochem. Pharmacol."},{"key":"3897_CR55","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1124\/mol.116.105007","volume":"90","author":"AT Nguyen","year":"2016","unstructured":"Nguyen, A. T. et al. Extracellular loop 2 of the adenosine A1 receptor has a key role in orthosteric ligand affinity and agonist efficacy. Mol. Pharmacol. 90, 703\u2013714 (2016).","journal-title":"Mol. Pharmacol."},{"key":"3897_CR56","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":"3897_CR57","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1126\/science.aaa5264","volume":"348","author":"RO Dror","year":"2015","unstructured":"Dror, R. O. et al. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science 348, 1361\u20131365 (2015).","journal-title":"Science"},{"key":"3897_CR58","doi-asserted-by":"publisher","first-page":"18684","DOI":"10.1073\/pnas.1110499108","volume":"108","author":"RO Dror","year":"2011","unstructured":"Dror, R. O. et al. Activation mechanism of the \u03b22-adrenergic receptor. Proc. Natl Acad. Sci. USA 108, 18684\u201318689 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3897_CR59","doi-asserted-by":"publisher","first-page":"6462","DOI":"10.1021\/acs.jpcb.9b04867","volume":"123","author":"J Wang","year":"2019","unstructured":"Wang, J. & Miao, Y. Mechanistic insights into specific G protein interactions with adenosine receptors. J. Phys. Chem. B 123, 6462\u20136473 (2019).","journal-title":"J. Phys. Chem. B"},{"key":"3897_CR60","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","volume":"14","author":"W Humphrey","year":"1996","unstructured":"Humphrey, W., Dalke, A. & Schulten, K. VMD: xisual molecular dynamics. J. Mol. Graph. 14, 33\u201338 (1996).","journal-title":"J. Mol. Graph."},{"key":"3897_CR61","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.bbagen.2014.08.004","volume":"1850","author":"K Vanommeslaeghe","year":"2015","unstructured":"Vanommeslaeghe, K. & MacKerell, A. D. CHARMM additive and polarizable force fields for biophysics and computer-aided drug design. Biochim. Biophys. Acta 1850, 861\u2013871 (2015).","journal-title":"Biochim. Biophys. Acta"},{"key":"3897_CR62","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nmeth.4067","volume":"14","author":"J Huang","year":"2016","unstructured":"Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71\u201373 (2016).","journal-title":"Nat. Methods"},{"key":"3897_CR63","doi-asserted-by":"publisher","first-page":"7830","DOI":"10.1021\/jp101759q","volume":"114","author":"JB Klauda","year":"2010","unstructured":"Klauda, J. B. et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 114, 7830\u20137843 (2010).","journal-title":"J. Phys. Chem. B"},{"key":"3897_CR64","doi-asserted-by":"publisher","first-page":"3144","DOI":"10.1021\/ci300363c","volume":"52","author":"K Vanommeslaeghe","year":"2012","unstructured":"Vanommeslaeghe, K. & MacKerell, A. D. Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing. J. Chem. Inf. Model. 52, 3144\u20133154 (2012).","journal-title":"J. Chem. Inf. Model."},{"key":"3897_CR65","doi-asserted-by":"publisher","first-page":"3155","DOI":"10.1021\/ci3003649","volume":"52","author":"K Vanommeslaeghe","year":"2012","unstructured":"Vanommeslaeghe, K., Raman, E. P. & MacKerell, A. D. Automation of the CHARMM General Force Field (CGenFF) II: assignment of bonded parameters and partial atomic charges. J. Chem. Inf. Model. 52, 3155\u20133168 (2012).","journal-title":"J. Chem. Inf. Model."},{"key":"3897_CR66","doi-asserted-by":"publisher","first-page":"12162","DOI":"10.1073\/pnas.1614538113","volume":"113","author":"Y Miao","year":"2016","unstructured":"Miao, Y. & McCammon, J. A. Graded activation and free energy landscapes of a muscarinic G-protein\u2013coupled receptor. Proc. Natl Acad. Sci. USA 113, 12162\u201312167 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3897_CR67","doi-asserted-by":"publisher","first-page":"3036","DOI":"10.1073\/pnas.1800756115","volume":"115","author":"Y Miao","year":"2018","unstructured":"Miao, Y. & McCammon, J. A. Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor. Proc. Natl Acad. Sci. USA 115, 3036\u20133041 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3897_CR68","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1002\/jcc.20289","volume":"26","author":"JC Phillips","year":"2005","unstructured":"Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781\u20131802 (2005).","journal-title":"J. Comput. Chem."},{"key":"3897_CR69","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","volume":"98","author":"T Darden","year":"1993","unstructured":"Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an N\u22c5log(N) method for Ewald sums in large systems. J. Chem. Phys., 98, 10089 (1993).","journal-title":"J. Chem. Phys."},{"key":"3897_CR70","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","volume":"23","author":"J-P Ryckaert","year":"1977","unstructured":"Ryckaert, J.-P., Ciccotti, G. & Berendsen, H. J. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 23, 327\u2013341 (1977).","journal-title":"J. Comput. Phys."},{"key":"3897_CR71","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1039\/C1CP22600B","volume":"14","author":"N Bernstein","year":"2012","unstructured":"Bernstein, N. et al. QM\/MM simulation of liquid water with an adaptive quantum region. Phys. Chem. Chem. Phys. 14, 646\u2013656 (2012).","journal-title":"Phys. Chem. Chem. Phys."},{"key":"3897_CR72","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1021\/ct400341p","volume":"9","author":"DR Roe","year":"2013","unstructured":"Roe, D. R. & Cheatham, T. E. PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 9, 3084\u20133095 (2013).","journal-title":"J. Chem. Theory Comput."},{"key":"3897_CR73","doi-asserted-by":"publisher","first-page":"7682","DOI":"10.1073\/pnas.0611448104","volume":"104","author":"MR Whorton","year":"2007","unstructured":"Whorton, M. R. et al. A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc. Natl Acad. Sci. USA 104, 7682\u20137687 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-03897-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-03897-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-03897-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T08:11:33Z","timestamp":1675671093000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-021-03897-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,8]]},"references-count":73,"journal-issue":{"issue":"7877","published-print":{"date-parts":[[2021,9,23]]}},"alternative-id":["3897"],"URL":"https:\/\/doi.org\/10.1038\/s41586-021-03897-2","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,8]]},"assertion":[{"value":"6 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2021","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"}}]}}