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

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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MOLECULAR EVOLUTION OF GPCRS: Melanocortin/melanocortin receptors

Journal of Molecular Endocrinology ◽

10.1530/jme-14-0050 ◽

2014 ◽

Vol 52 (3) ◽

pp. T29-T42 ◽

Cited By ~ 49

Author(s):

Robert M Dores ◽

Richard L Londraville ◽

Jeremy Prokop ◽

Perry Davis ◽

Nathan Dewey ◽

...

Keyword(s):

Energy Homeostasis ◽

Focal Point ◽

Cartilaginous Fish ◽

G Protein Coupled Receptors ◽

Melanocortin Receptors ◽

Accessory Proteins ◽

Melanocortin 1 Receptor ◽

Ligand Selectivity ◽

G Protein Coupled ◽

Receptor Accessory Protein

The melanocortin receptors (MCRs) are a family of G protein-coupled receptors that are activated by melanocortin ligands derived from the proprotein, proopiomelanocortin (POMC). During the radiation of the gnathostomes, the five receptors have become functionally segregated (i.e. melanocortin 1 receptor (MC1R), pigmentation regulation; MC2R, glucocorticoid synthesis; MC3R and MC4R, energy homeostasis; and MC5R, exocrine gland physiology). A focus of this review is the role that ligand selectivity plays in the hypothalamus/pituitary/adrenal–interrenal (HPA–I) axis of teleosts and tetrapods as a result of the exclusive ligand selectivity of MC2R for the ligand ACTH. A second focal point of this review is the roles that the accessory proteins melanocortin 2 receptor accessory protein 1 (MRAP1) and MRAP2 are playing in, respectively, the HPA–I axis (MC2R) and the regulation of energy homeostasis by neurons in the hypothalamus (MC4R) of teleosts and tetrapods. In addition, observations are presented on trends in the ligand selectivity parameters of cartilaginous fish, teleost, and tetrapod MC1R, MC3R, MC4R, and MC5R paralogs, and the modeling of the HFRW motif of ACTH(1–24) when compared with α-MSH. The radiation of the MCRs during the evolution of the gnathostomes provides examples of how the physiology of endocrine and neuronal circuits can be shaped by ligand selectivity, the intersession of reverse agonists (agouti-related peptides (AGRPs)), and interactions with accessory proteins (MRAPs).

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Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis

Hormones and Behavior ◽

10.1016/j.yhbeh.2014.02.004 ◽

2014 ◽

Vol 66 (1) ◽

pp. 196-207 ◽

Cited By ~ 50

Author(s):

Kathryn E. Davis ◽

Elizabeth J. Carstens ◽

Boman G. Irani ◽

Lana M. Gent ◽

Lisa M. Hahner ◽

...

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Energy Homeostasis ◽

Sexually Dimorphic ◽

G Protein Coupled

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Role of G Protein-Coupled Receptor Kinases in the Homologous Desensitization of the Human and Mouse Melanocortin 1 Receptors

Molecular Endocrinology ◽

10.1210/me.2004-0227 ◽

2005 ◽

Vol 19 (4) ◽

pp. 1035-1048 ◽

Cited By ~ 24

Author(s):

Jesús Sánchez-Más ◽

Lidia A. Guillo ◽

Paola Zanna ◽

Celia Jiménez-Cervantes ◽

José C. García-Borrón

Keyword(s):

Protein Kinase ◽

G Protein ◽

Skin Pigmentation ◽

Melanoma Cells ◽

Dominant Negative ◽

G Protein Coupled Receptor ◽

Melanocortin 1 Receptor ◽

Proliferation And Differentiation ◽

G Protein Coupled ◽

Homologous Desensitization

Abstract The melanocortin 1 receptor, a G protein-coupled receptor positively coupled to adenylyl cyclase, is a key regulator of epidermal melanocyte proliferation and differentiation and a determinant of human skin phototype and skin cancer risk. Despite its potential importance for regulation of pigmentation, no information is available on homologous desensitization of this receptor. We found that the human melanocortin 1 receptor (MC1R) and its mouse ortholog (Mc1r) undergo homologous desensitization in melanoma cells. Desensitization is not dependent on protein kinase A, protein kinase C, calcium mobilization, or MAPKs, but is agonist dose-dependent. Both melanoma cells and normal melanocytes express two members of the G protein-coupled receptor kinase (GRK) family, GRK2 and GRK6. Cotransfection of the receptor and GRK2 or GRK6 genes in heterologous cells demonstrated that GRK2 and GRK6 impair agonist-dependent signaling by MC1R or Mc1r. However, GRK6, but not GRK2, was able to inhibit MC1R agonist-independent constitutive signaling. Expression of a dominant negative GRK2 mutant in melanoma cells increased their cAMP response to agonists. Agonist-stimulated cAMP production decreased in melanoma cells enriched with GRK6 after stable transfection. Therefore, GRK2 and GRK6 seem to be key regulators of melanocortin 1 receptor signaling and may be important determinants of skin pigmentation.

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Molecular mechanism of biased signaling in a prototypical G protein–coupled receptor

Science ◽

10.1126/science.aaz0326 ◽

2020 ◽

Vol 367 (6480) ◽

pp. 881-887 ◽

Cited By ~ 21

Author(s):

Carl-Mikael Suomivuori ◽

Naomi R. Latorraca ◽

Laura M. Wingler ◽

Stephan Eismann ◽

Matthew C. King ◽

...

Keyword(s):

G Protein ◽

Protein A ◽

Binding Pocket ◽

Great Promise ◽

G Protein Coupled Receptor ◽

Structural Mechanism ◽

Biased Signaling ◽

Dynamics Simulations ◽

Effective Drugs ◽

G Protein Coupled

Biased signaling, in which different ligands that bind to the same G protein–coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.

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Faculty Opinions recommendation of Obestatin induction of early-response gene expression in gastrointestinal and adipose tissues and the mediatory role of G protein-coupled receptor, GPR39.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1117805.573887 ◽

2008 ◽

Author(s):

Willis Samson

Keyword(s):

Gene Expression ◽

G Protein ◽

Early Response ◽

G Protein Coupled Receptor ◽

Response Gene ◽

Adipose Tissues ◽

Early Response Gene ◽

G Protein Coupled

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Marijuana and β-estradiol interactions on spatial learning and memory in young female rats: Lack of role of the G protein-coupled estrogen receptor (GPR30)

Life Sciences ◽

10.1016/j.lfs.2021.119723 ◽

2021 ◽

pp. 119723

Author(s):

Mohadeseh Chahkandi ◽

Gholamreza Komeili ◽

Gholamreza Sepehri ◽

Mohammad Khaksari ◽

Sedigheh Amiresmaili

Keyword(s):

Estrogen Receptor ◽

Learning And Memory ◽

G Protein ◽

Spatial Learning ◽

Young Female ◽

Female Rats ◽

Spatial Learning And Memory ◽

G Protein Coupled

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The melanocortin system

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00434.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. E468-E474 ◽

Cited By ~ 264

Author(s):

Ira Gantz ◽

Tung M. Fong

Keyword(s):

Sexual Function ◽

Energy Homeostasis ◽

Melanocortin Receptors ◽

Experimental Basis ◽

Melanocortin System ◽

Genetic Studies ◽

Melanocortin Peptides ◽

Selective Agonists ◽

Made In

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.

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