{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:17:58Z","timestamp":1789564678317,"version":"build-2803163510"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Res"],"published-print":{"date-parts":[[2021,11]]},"DOI":"10.1038\/s41422-021-00552-3","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T06:46:44Z","timestamp":1629874004000},"page":"1163-1175","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Structural insights into ligand recognition and activation of the melanocortin-4 receptor"],"prefix":"10.1038","volume":"31","author":[{"given":"Huibing","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Nan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3028-3243","authenticated-orcid":false,"given":"Dehua","family":"Yang","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\/0000-0001-6602-7116","authenticated-orcid":false,"given":"Qingya","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8757-4602","authenticated-orcid":false,"given":"Dan-Dan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antao","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-8169","authenticated-orcid":false,"given":"Shanshan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Peng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Scharf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingjun","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhua","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6550-9017","authenticated-orcid":false,"given":"Ming-Wei","family":"Wang","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":[[2021,8,25]]},"reference":[{"key":"552_CR1","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/nn.4202","volume":"19","author":"MJ Krashes","year":"2016","unstructured":"Krashes, M. J., Lowell, B. B. & Garfield, A. S. Melanocortin-4 receptor-regulated energy homeostasis. Nat. Neurosci. 19, 206\u2013219 (2016).","journal-title":"Nat. Neurosci."},{"key":"552_CR2","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1210\/er.2009-0037","volume":"31","author":"YX Tao","year":"2010","unstructured":"Tao, Y. X. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr. Rev. 31, 506\u2013543 (2010).","journal-title":"Endocr. Rev."},{"key":"552_CR3","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.molmed.2018.12.002","volume":"25","author":"P Kuhnen","year":"2019","unstructured":"Kuhnen, P., Krude, H. & Biebermann, H. Melanocortin-4 receptor signalling: importance for weight regulation and obesity treatment. Trends Mol. Med. 25, 136\u2013148 (2019).","journal-title":"Trends Mol. Med."},{"key":"552_CR4","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/s41588-017-0020-9","volume":"50","author":"JE Siljee","year":"2018","unstructured":"Siljee, J. E. et al. Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat. Genet. 50, 180\u2013185 (2018).","journal-title":"Nat. Genet."},{"key":"552_CR5","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/B978-0-12-386933-3.00005-4","volume":"114","author":"A Hinney","year":"2013","unstructured":"Hinney, A., Volckmar, A. L. & Knoll, N. Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis. Prog. Mol. Biol. Transl. Sci. 114, 147\u2013191 (2013).","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"552_CR6","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.ejphar.2010.12.020","volume":"660","author":"Y Yang","year":"2011","unstructured":"Yang, Y. Structure, function and regulation of the melanocortin receptors. Eur. J. Pharmacol. 660, 125\u2013130 (2011).","journal-title":"Eur. J. Pharmacol."},{"key":"552_CR7","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/2407","volume":"20","author":"C Vaisse","year":"1998","unstructured":"Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113\u2013114 (1998).","journal-title":"Nat. Genet."},{"key":"552_CR8","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.cell.2019.03.044","volume":"177","author":"LA Lotta","year":"2019","unstructured":"Lotta, L. A. et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell 177, 597\u2013607.e9 (2019).","journal-title":"Cell"},{"key":"552_CR9","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1056\/NEJMoa021971","volume":"348","author":"R Branson","year":"2003","unstructured":"Branson, R. et al. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N. Engl. J. Med. 348, 1096\u20131103 (2003).","journal-title":"N. Engl. J. Med."},{"key":"552_CR10","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1016\/j.molmet.2017.06.015","volume":"6","author":"TH Collet","year":"2017","unstructured":"Collet, T. H. et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol. Metab. 6, 1321\u20131329 (2017).","journal-title":"Mol. Metab."},{"key":"552_CR11","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.tips.2018.01.004","volume":"39","author":"JPL Goncalves","year":"2018","unstructured":"Goncalves, J. P. L., Palmer, D. & Meldal, M. MC4R agonists: structural overview on antiobesity therapeutics. Trends Pharmacol. Sci. 39, 402\u2013423 (2018).","journal-title":"Trends Pharmacol. Sci."},{"key":"552_CR12","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.mce.2010.07.015","volume":"331","author":"SN Cooray","year":"2011","unstructured":"Cooray, S. N. & Clark, A. J. Melanocortin receptors and their accessory proteins. Mol. Cell. Endocrinol. 331, 215\u2013221 (2011).","journal-title":"Mol. Cell. Endocrinol."},{"key":"552_CR13","doi-asserted-by":"publisher","first-page":"8246","DOI":"10.1016\/S0021-9258(18)53088-X","volume":"268","author":"I Gantz","year":"1993","unstructured":"Gantz, I. et al. Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246\u20138250 (1993).","journal-title":"J. Biol. Chem."},{"key":"552_CR14","doi-asserted-by":"publisher","first-page":"eaat0866","DOI":"10.1126\/sciadv.aat0866","volume":"4","author":"M Ghamari-Langroudi","year":"2018","unstructured":"Ghamari-Langroudi, M. et al. Regulation of energy rheostasis by the melanocortin-3 receptor. Sci. Adv. 4, eaat0866 (2018).","journal-title":"Sci. Adv."},{"key":"552_CR15","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1210\/endo.139.5.6008","volume":"139","author":"M van der Kraan","year":"1998","unstructured":"van der Kraan, M. et al. Expression of melanocortin-5 receptor in secretory epithelia supports a functional role in exocrine and endocrine glands. Endocrinology 139, 2348\u20132355 (1998).","journal-title":"Endocrinology"},{"key":"552_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1124\/pr.56.1.1","volume":"56","author":"A Catania","year":"2004","unstructured":"Catania, A., Gatti, S., Colombo, G. & Lipton, J. M. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol. Rev. 56, 1\u201329 (2004).","journal-title":"Pharmacol. Rev."},{"key":"552_CR17","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1210\/er.2006-0034","volume":"27","author":"RD Cone","year":"2006","unstructured":"Cone, R. D. Studies on the physiological functions of the melanocortin system. Endocr. Rev. 27, 736\u2013749 (2006).","journal-title":"Endocr. Rev."},{"key":"552_CR18","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/ng1501","volume":"37","author":"LA Metherell","year":"2005","unstructured":"Metherell, L. A. et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat. Genet. 37, 166\u2013170 (2005).","journal-title":"Nat. Genet."},{"key":"552_CR19","doi-asserted-by":"publisher","first-page":"T29","DOI":"10.1530\/JME-14-0050","volume":"52","author":"RM Dores","year":"2014","unstructured":"Dores, R. M. et al. Molecular evolution of GPCRs: Melanocortin\/melanocortin receptors. J. Mol. Endocrinol. 52, T29\u2013T42 (2014).","journal-title":"J. Mol. Endocrinol."},{"key":"552_CR20","doi-asserted-by":"publisher","first-page":"4035","DOI":"10.1021\/jm058241a","volume":"49","author":"RP Nargund","year":"2006","unstructured":"Nargund, R. P., Strack, A. M. & Fong, T. M. Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J. Med. Chem. 49, 4035\u20134043 (2006).","journal-title":"J. Med. Chem."},{"key":"552_CR21","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1021\/jm030452x","volume":"47","author":"G Han","year":"2004","unstructured":"Han, G. et al. De novo design, synthesis, and pharmacology of alpha-melanocyte stimulating hormone analogues derived from somatostatin by a hybrid approach. J. Med. Chem. 47, 1514\u20131526 (2004).","journal-title":"J. Med. Chem."},{"key":"552_CR22","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.1021\/jm00132a010","volume":"32","author":"F Al-Obeidi","year":"1989","unstructured":"Al-Obeidi, F., Castrucci, A. M., Hadley, M. E. & Hruby, V. J. Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J. Med. Chem. 32, 2555\u20132561 (1989).","journal-title":"J. Med. Chem."},{"key":"552_CR23","doi-asserted-by":"publisher","first-page":"3454","DOI":"10.1021\/jm00018a005","volume":"38","author":"VJ Hruby","year":"1995","unstructured":"Hruby, V. J. et al. Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J. Med. Chem. 38, 3454\u20133461 (1995).","journal-title":"J. Med. Chem."},{"key":"552_CR24","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1002\/med.10064","volume":"24","author":"JR Holder","year":"2004","unstructured":"Holder, J. R. & Haskell-Luevano, C. Melanocortin ligands: 30 years of structure-activity relationship (SAR) studies. Med. Res. Rev. 24, 325\u2013356 (2004).","journal-title":"Med. Res. Rev."},{"key":"552_CR25","unstructured":"Sebhat, I. K. et al. Design and pharmacology of N-[(3R)\u22121,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)\u22121-(4-chlorobenzyl)\u2212 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]\u22122-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist. J. Med. Chem. 45, 4589\u20134593 (2002)."},{"key":"552_CR26","unstructured":"Ye, Z. et al. Discovery and activity of (1R,4S,6R)-N-[(1R)\u22122-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]\u22121-piper idinyl]\u22121-[(4-fluorophenyl)methyl]\u22122-oxoethyl]\u22122-methyl-2-azabicyclo[2.2.2]octane \u22126-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist. Bioorg. Med. Chem. Lett. 15, 3501\u20133505 (2005)."},{"key":"552_CR27","doi-asserted-by":"publisher","first-page":"eaau0629","DOI":"10.1126\/science.aau0629","volume":"363","author":"N Matharu","year":"2019","unstructured":"Matharu, N. et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363, eaau0629 (2019).","journal-title":"Science"},{"key":"552_CR28","doi-asserted-by":"publisher","first-page":"5754","DOI":"10.1073\/pnas.77.10.5754","volume":"77","author":"TK Sawyer","year":"1980","unstructured":"Sawyer, T. K. et al. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc. Natl. Acad. Sci. USA 77, 5754\u20135758 (1980).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"552_CR29","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1007\/s40265-019-01187-w","volume":"79","author":"S Dhillon","year":"2019","unstructured":"Dhillon, S. & Keam, S. J. Bremelanotide: first approval. Drugs 79, 1599\u20131606 (2019).","journal-title":"Drugs"},{"key":"552_CR30","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1038\/s41587-019-0347-0","volume":"37","author":"M Ratner","year":"2019","unstructured":"Ratner, M. Patients with porphyria bask in sunlight of FDA approval. Nat. Biotechnol. 37, 1390\u20131391 (2019).","journal-title":"Nat. Biotechnol."},{"key":"552_CR31","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1021\/acsptsci.8b00017","volume":"1","author":"Y-L Liang","year":"2018","unstructured":"Liang, Y.-L. et al. Dominant negative G proteins enhance formation and purification of agonist-GPCR-G protein complexes for structure determination. ACS Pharmacol. Transl. Sci.1, 12\u201320 (2018).","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"552_CR32","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nature25773","volume":"555","author":"Y-L Liang","year":"2018","unstructured":"Liang, Y.-L. et al. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555, 121\u2013125 (2018).","journal-title":"Nature"},{"key":"552_CR33","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":"552_CR34","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-Gs protein complex. Nature 477, 549\u2013555 (2011).","journal-title":"Nature"},{"key":"552_CR35","doi-asserted-by":"crossref","unstructured":"Ballesteros, J. A. & Weinstein, H. in Methods in Neurosciences Vol. 25 (ed. Sealfon, S. C.) 366\u2013428 (Academic Press, 1995).","DOI":"10.1016\/S1043-9471(05)80049-7"},{"key":"552_CR36","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1146\/annurev-biochem-060614-033910","volume":"87","author":"WI Weis","year":"2018","unstructured":"Weis, W. I. & Kobilka, B. K. The molecular basis of G protein-coupled receptor activation. Ann. Rev. Biochem. 87, 897\u2013919 (2018).","journal-title":"Ann. Rev. Biochem."},{"key":"552_CR37","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1016\/j.cell.2015.06.002","volume":"161","author":"JE Chrencik","year":"2015","unstructured":"Chrencik, J. E. et al. Crystal structure of antagonist bound human lysophosphatidic acid receptor 1. Cell 161, 1633\u20131643 (2015).","journal-title":"Cell"},{"key":"552_CR38","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/j.cell.2016.10.004","volume":"167","author":"T Hua","year":"2016","unstructured":"Hua, T. et al. Crystal structure of the human cannabinoid receptor CB1. Cell 167, 750\u2013762.e14 (2016).","journal-title":"Cell"},{"key":"552_CR39","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1038\/nature23272","volume":"547","author":"T Hua","year":"2017","unstructured":"Hua, T. et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 547, 468\u2013471 (2017).","journal-title":"Nature"},{"key":"552_CR40","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\u2013G protein complex. Cell 176, 448\u2013458.e12 (2019).","journal-title":"Cell"},{"key":"552_CR41","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.cell.2020.01.008","volume":"180","author":"T Hua","year":"2020","unstructured":"Hua, T. et al. Activation and signaling mechanism revealed by cannabinoid receptor-Gi complex structures. Cell 180, 655\u2013665.e18 (2020).","journal-title":"Cell"},{"key":"552_CR42","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1126\/science.1215904","volume":"335","author":"MA Hanson","year":"2012","unstructured":"Hanson, M. A. et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851\u2013855 (2012).","journal-title":"Science"},{"key":"552_CR43","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1126\/science.aaz8995","volume":"368","author":"J Yu","year":"2020","unstructured":"Yu, J. et al. Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding. Science 368, 428\u2013433 (2020).","journal-title":"Science"},{"key":"552_CR44","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/nature14663","volume":"524","author":"T Flock","year":"2015","unstructured":"Flock, T. et al. Universal allosteric mechanism for G\u03b1 activation by GPCRs. Nature 524, 173\u2013179 (2015).","journal-title":"Nature"},{"key":"552_CR45","doi-asserted-by":"publisher","first-page":"14900","DOI":"10.1021\/bi001684q","volume":"39","author":"YK Yang","year":"2000","unstructured":"Yang, Y. K. et al. Molecular determinants of ligand binding to the human melanocortin-4 receptor. Biochemistry 39, 14900\u201314911 (2000).","journal-title":"Biochemistry"},{"key":"552_CR46","doi-asserted-by":"publisher","first-page":"20328","DOI":"10.1074\/jbc.M201343200","volume":"277","author":"Y Yang","year":"2002","unstructured":"Yang, Y. et al. Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity. J. Biol. Chem. 277, 20328\u201320335 (2002).","journal-title":"J. Biol. Chem."},{"key":"552_CR47","doi-asserted-by":"publisher","first-page":"e50279","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":"552_CR48","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nature09648","volume":"469","author":"SG Rasmussen","year":"2011","unstructured":"Rasmussen, S. G. et al. Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor. Nature 469, 175\u2013180 (2011).","journal-title":"Nature"},{"key":"552_CR49","doi-asserted-by":"publisher","first-page":"e35946","DOI":"10.7554\/eLife.35946","volume":"7","author":"J Garcia-Nafria","year":"2018","unstructured":"Garcia-Nafria, J., Lee, Y., Bai, X., Carpenter, B. & Tate, C. G. Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein. Elife 7, e35946 (2018).","journal-title":"Elife"},{"key":"552_CR50","doi-asserted-by":"publisher","first-page":"3446","DOI":"10.1021\/jm400140q","volume":"56","author":"JA Christopher","year":"2013","unstructured":"Christopher, J. A. et al. Biophysical fragment screening of the \u03b21-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design. J. Med. Chem. 56, 3446\u20133455 (2013).","journal-title":"J. Med. Chem."},{"key":"552_CR51","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.molcel.2020.08.001","volume":"80","author":"M Su","year":"2020","unstructured":"Su, M. et al. Structural basis of the activation of heterotrimeric Gs-protein by isoproterenol-bound \u03b2(1)-adrenergic receptor. Mol. Cell 80, 59\u201371.e4 (2020).","journal-title":"Mol. Cell"},{"key":"552_CR52","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1107\/S2052252519013137","volume":"6","author":"A Ishchenko","year":"2019","unstructured":"Ishchenko, A. et al. Toward G protein-coupled receptor structure-based drug design using X-ray lasers. IUCrJ 6, 1106\u20131119 (2019).","journal-title":"IUCrJ"},{"key":"552_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-76277-x","volume":"10","author":"K Ihara","year":"2020","unstructured":"Ihara, K. et al. Isoprenoid-chained lipid EROCOC17+4: a new matrix for membrane protein crystallization and a crystal delivery medium in serial femtosecond crystallography. Sci. Rep. 10, 19305 (2020).","journal-title":"Sci. Rep."},{"key":"552_CR54","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.str.2020.11.007","volume":"29","author":"S Nojima","year":"2020","unstructured":"Nojima, S. et al. Cryo-EM structure of the prostaglandin E receptor EP4 coupled to G protein. Structure 29, 252\u2013260 (2020).","journal-title":"Structure"},{"key":"552_CR55","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s41589-018-0131-3","volume":"15","author":"Y Toyoda","year":"2019","unstructured":"Toyoda, Y. et al. Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface. Nat. Chem. Biol. 15, 18\u201326 (2019).","journal-title":"Nat. Chem. Biol."},{"key":"552_CR56","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s41586-020-2569-1","volume":"587","author":"F Yang","year":"2020","unstructured":"Yang, F. et al. Structural basis of GPBAR activation and bile acid recognition. Nature 587, 499\u2013504 (2020).","journal-title":"Nature"},{"key":"552_CR57","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1056\/NEJMoa022050","volume":"348","author":"IS Farooqi","year":"2003","unstructured":"Farooqi, I. S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348, 1085\u20131095 (2003).","journal-title":"N. Engl. J. Med."},{"key":"552_CR58","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mce.2005.04.012","volume":"239","author":"YX Tao","year":"2005","unstructured":"Tao, Y. X. Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol. Cell. Endocrinol. 239, 1\u201314 (2005).","journal-title":"Mol. Cell. Endocrinol."},{"key":"552_CR59","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1126\/science.abf7958","volume":"372","author":"Hadar Israeli","year":"2021","unstructured":"Hadar Israeli et al. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling. Science 372, 808\u2013814 (2021).","journal-title":"Science"},{"key":"552_CR60","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":"552_CR61","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":"552_CR62","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.jsb.2012.09.006","volume":"180","author":"SH Scheres","year":"2012","unstructured":"Scheres, S. H. RELION: implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180, 519\u2013530 (2012).","journal-title":"J. Struct. Biol."},{"key":"552_CR63","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1002\/pro.3293","volume":"27","author":"JB Heymann","year":"2018","unstructured":"Heymann, J. B. Guidelines for using Bsoft for high resolution reconstruction and validation of biomolecular structures from electron micrographs. Protein Sci. 27, 159\u2013171 (2018).","journal-title":"Protein Sci."},{"key":"552_CR64","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1126\/science.aav7942","volume":"364","author":"LH Zhao","year":"2019","unstructured":"Zhao, L. H. et al. Structure and dynamics of the active human parathyroid hormone receptor-1. Science 364, 148\u2013153 (2019).","journal-title":"Science"},{"key":"552_CR65","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":"552_CR66","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, Biol. Crystallogr. 66, 213\u2013221 (2010).","journal-title":"Acta Crystallogr. D, Biol. Crystallogr."},{"key":"552_CR67","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1002\/pro.3235","volume":"27","author":"TD Goddard","year":"2018","unstructured":"Goddard, T. D. et al. UCSF ChimeraX: Meeting modern challenges in visualization and analysis. Protein Sci. 27, 14\u201325 (2018).","journal-title":"Protein Sci."},{"key":"552_CR68","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":"552_CR69","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/978-1-61779-465-0_10","volume":"819","author":"G Lemmon","year":"2012","unstructured":"Lemmon, G. & Meiler, J. Rosetta Ligand docking with flexible XML protocols. Methods Mol. Biol. 819, 143\u2013155 (2012).","journal-title":"Methods Mol. Biol."},{"key":"552_CR70","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.jmb.2008.11.010","volume":"385","author":"IW Davis","year":"2009","unstructured":"Davis, I. W. & Baker, D. RosettaLigand docking with full ligand and receptor flexibility. J. Mol. Biol. 385, 381\u2013392 (2009).","journal-title":"J. Mol. Biol."},{"key":"552_CR71","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-3-33","volume":"3","author":"NM O\u2019Boyle","year":"2011","unstructured":"O\u2019Boyle, N. M. et al. Open Babel: an open chemical toolbox. J. Cheminform. 3, 33 (2011).","journal-title":"J. Cheminform."}],"container-title":["Cell Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41422-021-00552-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-021-00552-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41422-021-00552-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T05:13:47Z","timestamp":1635830027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41422-021-00552-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,25]]},"references-count":71,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["552"],"URL":"https:\/\/doi.org\/10.1038\/s41422-021-00552-3","relation":{},"ISSN":["1001-0602","1748-7838"],"issn-type":[{"value":"1001-0602","type":"print"},{"value":"1748-7838","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,25]]},"assertion":[{"value":"22 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 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"}}]}}