Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling

Israeli, Hadar; Degtjarik, Oksana; Fierro, Fabrizio; Chunilal, Vidicha; Gill, Amandeep Kaur; Roth, Nicolas; Botta, Joaquín; Prabahar, Vadivel; Peleg, Yoav; Chan, Li F.; Ben‐Zvi, Danny; McCormick, Peter J.; Niv, Masha Y.; Shalev-Benami, Moran

doi:10.1126/science.abf7958

Cited by 76 publications

(75 citation statements)

References 86 publications

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“…The binding mode between three peptides and MC1R is similar to that of recently reported setmelanotide-MC4R-Gs complex (Supplementary information, Fig. S6j), indicating a conserved mechanism of ligand recognition by different family members of melanocortin receptors 27 .…”

Section: Discussionsupporting

confidence: 82%

“…M128 3.36 L mutation of compromised SHU9119-stimulated cAMP response of MC1R (Supplementary information, Fig. S5a and Table S5), consistent with that L133 3.36 M mutation of MC4R converted SHU9119 from an antagonist to a partial agonist 27,39 . Together, these results provide a basis of SHU9119 as an agonist for MC1R and as an antagonist for MC4R.…”

Section: Differential Activities Of Peptide Ligandssupporting

confidence: 79%

“…MC5R is commonly seen in peripheral tissues and regulates exocrine gland secretion such as lacrimal, preputial and harderian glands 25 . However, structural basis for the complex interplay between melanocortins and MC1R-MC5R is largely unknown, except for the recent studies on MC4R [26][27][28] .Given the important physiological functions of the melanocortin system, diverse synthetic ligands have been developed for therapeutic applications (Fig. 1a).…”

mentioning

confidence: 99%

“…SHU9119, a cyclic α-MSH analog, is a partial agonist for MC1R and MC5R but acts as an antagonist for MC3R and MC4R 31,32 . Currently, only the inactive crystal structure of MC4R bound to SHU9119 and the active cryo-electron microscopy (cryo-EM) structures of the MC4R-Gs complexes are available [26][27][28] . The limited structural information of the melanocortin system has hindered our understanding of the detailed mechanism by which various endogenous and synthetic peptides exert their differentiated actions.…”

mentioning

confidence: 99%

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Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor

Chen

Dai

et al. 2021

Preprint

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Melanocortins are peptide hormones critical for stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R to MC5R), predominately through the stimulatory G protein (Gs). MC1R, the founding member of melanocortin receptors, is mainly expressed in melanocytes and is involved in melanogenesis. Dysfunction of MC1R is associated with the development of melanoma and skin cancer. Here we present three cryo-electron microscopy structures of the MC1R-Gs complexes bound to endogenous hormone α-MSH, a marketed drug afamelanotide, and a synthetic agonist SHU9119. These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding. They also demonstrate the basis of differential activities among different ligands. In addition, unexpected interactions between MC1R and the Gβ subunit were discovered from these structures. Together, our results provide a conserved mechanism of calcium-mediated ligand recognition, specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.

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Section: Discussionsupporting

confidence: 82%

Section: Differential Activities Of Peptide Ligandssupporting

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor

Chen

Dai

et al. 2021

Preprint

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“…G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors in eukaryotic cells. These seven-transmembrane receptors have influence in physiological events such as cell to cell communication, immune responses, nerve transmission and even hunger and sleep regulation [1][2][3]. The role of GPCRs in diseases such as rheumatoid arthritis, heart disease, cancer, obesity, and neurodegenerative disorders accentuates the need to investigate this family of receptors further.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization

et al. 2021

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G-protein coupled receptors (GPCRs) are known to form homo- and hetero- oligomers which are considered critical to modulate their function. However, studying the existence and functional implication of these complexes is not straightforward as controversial results are obtained depending on the method of analysis employed. Here, we use a quantitative single molecule super-resolution imaging technique named qPAINT to quantify complex formation within an example GPCR. qPAINT, based upon DNA-PAINT, takes advantage of the binding kinetics between fluorescently labelled DNA imager strands to complementary DNA docking strands coupled to protein targeting antibodies to quantify the protein copy number in nanoscale dimensions. We demonstrate qPAINT analysis via a novel pipeline to study the oligomerization of the purinergic receptor Y2 (P2Y2), a rhodopsin-like GPCR, highly expressed in the pancreatic cancer cell line AsPC-1, under control, agonistic and antagonistic conditions. Results reveal that whilst the density of P2Y2 receptors remained unchanged, antagonistic conditions displayed reduced percentage of oligomers, and smaller numbers of receptors in complexes. Yet, the oligomeric state of the receptors was not affected by agonist treatment, in line with previous reports. Understanding P2Y2 oligomerization under agonistic and antagonistic conditions will contribute to unravelling P2Y2 mechanistic action and therapeutic targeting.

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The role of metal ions in G protein‐coupled receptor signalling and drug discovery

Zou

Chan

et al. 2021

WIREs Comput Mol Sci

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Metal ions, such as Na+, Mg2+, Ca2+, and Zn2+, are highly abundant in biological systems. For many G protein‐coupled receptors (GPCRs), metal ions, especially Na+, have been found to stabilize the receptors' inactivate state preventing receptor activation. Besides this role, recent studies indicated that metal ions can modulate ligand–GPCR interactions allosterically. These findings on ion‐mediated GPCR signaling open new vistas for understanding the functioning of GPCRs and further could help in designing potent therapeutic compounds targeting GPCRs. Here we report on recent findings about role of orthosteric and allosteric metal ions in GPCR signaling and drug discovery. This article is categorized under: Structure and Mechanism > Molecular Structures Molecular and Statistical Mechanics > Molecular Mechanics Molecular and Statistical Mechanics > Molecular Interactions

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Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling

Cited by 76 publications

References 86 publications

Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor

Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor

Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization

The role of metal ions in G protein‐coupled receptor signalling and drug discovery

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