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Structural Insights Into Ligand Recognition and Activation of the Melanocortin-4

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Structural Insights Into Ligand Recognition and Activation of the Melanocortin-4 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.21.449233; this version posted June 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Structural insights into ligand recognition and activation of the melanocortin-4 2 receptor 3 Huibing Zhang1,2,3,4,#, Li-Nan Chen1,2,3,4,#, Dehua Yang5,6,7,#, Chunyou Mao1,2,3,4, Qingya 4 Shen1,2,3,4, Wenbo Feng8, Dan-Dan Shen1,2,3,4, Antao Dai5,6, Shanshan Xie9, Yan Zhou5,6, Jiao 5 Qin1,2,3,4, Jinpeng Sun10,11, Daniel H. Scharf12, Tingjun Hou13, Tianhua Zhou9, Ming-Wei 6 Wang5,6,7,8,14,15,* , Yan Zhang1,2,3,4,* 7 8 1Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang 9 University School of Medicine, Hangzhou 310058, Zhejiang, China 10 2Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China 11 3MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University 12 School of Medicine, Hangzhou 310058, Zhejiang, China 13 4Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou 310058, 14 Zhejiang, China 15 5The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy 16 of Sciences, Shanghai 201203, China 17 6The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of 18 Sciences, Shanghai 201203, China 19 7University of Chinese Academy of Sciences, Beijing 100049, China. 20 8School of Pharmacy, Fudan University, Shanghai, China 21 9Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University 22 School of Medicine, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, 23 China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 24 Zhejiang, China; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada 25 10Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; 26 Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China 27 11Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and 28 Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 29 Shandong, China 30 12Department of Microbiology and The Children’s Hospital, Zhejiang University School of Medicine, 31 Hangzhou 310058, Zhejiang, China 32 13Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of 33 Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China 34 14School of Life Science and Technology, ShanghaiTech University, Shanghai, China 35 15School of Basic Medical Sciences, Fudan University, Shanghai, China 36 #These authors contributed equally to this work. 37 *Correspondence: [email protected] (Y.Z.); [email protected] (M.-W.W.) 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.21.449233; this version posted June 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 38 SUMMARY 39 Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy 40 homeostasis. Its high sequence similarity to other MC receptor family members, low 41 agonist selectivity and the lack of structural information concerning receptor activation 42 have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, 43 we report four high-resolution structures of full-length MC4R in complex with the 44 heterotrimeric Gs protein stimulated by the endogenous peptide α-MSH, FDA- 45 approved drugs afamelanotide (Scenesse™) and bremelanotide (Vyleesi™), and 46 selective small-molecule ligand THIQ, respectively. Together with pharmacological 47 studies, our results reveal the conserved binding mode of peptidic agonists, the 48 distinctive molecular details of small-molecule agonist recognition underlying receptor 49 subtype selectivity, and distinct activation mechanism for MC4R, thereby offering new 50 insights into G protein coupling. Our work may facilitate the discovery of selective 51 therapeutic agents targeting MC4R. 52 53 INTRODUCTION 54 Melanocortin-4 receptor (MC4R), a key component of the leptin-melanocortin pathway, 55 acts at the intersection of homeostatic maintenance of energetic state.1-6 Mutations in 56 the MC4R gene were identified among patients with severe obesity from early 57 childhood.7,8 By far, natural occurring loss of function (LOF) MC4R mutations are the 58 most frequent monogenic cause of obesity or binge eating disorder.9 MC4R agonists 59 have been shown efficacious in appetite suppression, food intake reduction and body 60 weight loss in people with high BMI (body mass index) caused by leptin, 61 proopiomelanocortin (POMC) or MC4R deficiency.10 Obviously, MC4R plays a central 62 role in regulating energy balance and satiety, and is one of the best validated drug 63 targets for obesity.11 MC4R belongs to the melanocortin receptor family, a group of five 64 (MC1R − MC5R) class A G protein-coupled receptors (GPCRs) and is primarily 65 coupled to the stimulatory G protein (Gs) and increases intracellular cyclic adenosine 66 monophosphate (cAMP) accumulation.12 MC1R governs mammalian skin and hair 67 color by regulating the production of melanin.13 MC2R is mainly located in the adrenal 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.21.449233; this version posted June 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 68 cortex and controls the release of glucocorticoids.2 MC3R participates in the control of 69 energy homeostasis and is implicated in immune responses, natriuresis and circadian 70 rhythm.14 MC5R is involved in exocrine gland dysfunction, sebum regulation, and the 71 pathogenesis of acne.15-17 Except MC2R, which is only activated by ACTH 72 (adrenocorticotropic hormone) and requires an interplay with the melanocortin receptor 73 accessory protein (MRAP) to attain functionality,18 the other four MCRs are 74 endogenously activated by α-, β-, and γ-melanocyte-stimulating hormones (MSH), and 75 blocked by the natural inverse agonist agouti-related peptide (AgRP).19 These features 76 put forward a keen request for the development of a selective ligand for MC4R. 77 The endogenous ligands for MCRs contain a conserved His-Phe-Arg-Trp (HFRW) 78 motif necessary for receptor activation (Supplementary information, Table S1).20,21 79 Among them, α-MSH (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) 80 is the most well-studied peptide that has pleiotropic functions in pigmentation, 81 cardiovascular system, erectile ability, energy homeostasis and immune responses.21- 82 24 Driven by the pervasive issue of human obesity, tremendous efforts have been made 83 to design potent and selective therapeutic agents targeting MC4R, both of peptidic and 84 small-molecule nature.23-27 The linear peptide afamelanotide, Ac-Ser-Tyr-Ser-Nle4-Glu- 7 4 7 85 His-D-Phe -Arg-Trp-Gly-Lys-Pro-Val-NH2 (also known as [Nle , DPhe ]α-MSH, NDP- 86 α-MSH, melanotan-I, and MT-I), is capable of enhancing metabolic stability with 87 markedly improved potency compared to α-MSH.21,28 Subsequent efforts in obtaining 88 peptides with better bioactivities led to the discovery of a cyclic peptide agonist, Ac- 4 5 7 10 21,22 89 Nle -c [Asp , D-Phe , Lys ] α-MSH(4-10)-NH2 (melanotan-II, MT-II). Bremelanotide 90 (C-terminal OH-MT-II) was approved in 2019 by the FDA to treat premenopausal 91 women with sexual excitement dysfunction.29 Afamelanotide binds to MC1R in dermal 92 cells to ramp up melanin production, effectively tanning the skin, and as a photo 93 protectant received market approval in the European Union in 2014 and by the FDA in 94 2019.30 95 Unfortunately, owning to the high sequence homology among MCRs, most 96 peptidic agonists initially developed for MC4R lack the capability of avoiding cross- 97 reactivity with other MCR subtypes, such as MC1R, leading to adverse effects, e.g., 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.21.449233; this version posted June 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 98 skin pigmentation and nausea.10,23,29 Intriguingly, subtype selectivity of MC4R was first 99 achieved by a small-molecule agonist, THIQ, initially developed by Merck (1400-fold 100 vs. MC1R, 1200-fold vs. MC3R and 360-fold vs. MC5R),25 that significantly decreases 101 food consumption and simulates erectile responses. 102 The activation mechanism of MC4R and how it recognizes peptidic and small- 103 molecule agonists are poorly understood, hampering the structure-guided drug 104 discovery. Here, we employed single-particle cryo-electron microscopy (cryo-EM) to 105 determine four structures of the human MC4R-Gs complexes: three bound to α-MSH, 106 afamelanotide or bremelanotide at the resolutions of 3.0 Å, 3.0 Å and 3.1 Å, 107 respectively; and one bound to THIQ at the resolution of 3.1 Å (Fig. 1; Supplementary 108 information, Fig. S1, S2, Table S2). These structures reveal the molecular basis of 109 ligand recognition and receptor activation for MC4R, shed light on the subtype 110 selectivity of MCRs, and provide templates for the rational design of novel therapeutics 111 targeting MC4R to treat obesity.
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