Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective

The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (...

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Main Authors: Nicolas Heyder, Gunnar Kleinau, Michal Szczepek, Dennis Kwiatkowski, David Speck, Lucia Soletto, José Miguel Cerdá-Reverter, Heiko Krude, Peter Kühnen, Heike Biebermann, Patrick Scheerer
Format: Article
Language:English
Published: Frontiers Media S.A. 2019-07-01
Series:Frontiers in Endocrinology
Subjects:
MSH
Online Access:https://www.frontiersin.org/article/10.3389/fendo.2019.00515/full
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language English
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sources DOAJ
author Nicolas Heyder
Gunnar Kleinau
Michal Szczepek
Dennis Kwiatkowski
David Speck
Lucia Soletto
José Miguel Cerdá-Reverter
Heiko Krude
Peter Kühnen
Heike Biebermann
Patrick Scheerer
spellingShingle Nicolas Heyder
Gunnar Kleinau
Michal Szczepek
Dennis Kwiatkowski
David Speck
Lucia Soletto
José Miguel Cerdá-Reverter
Heiko Krude
Peter Kühnen
Heike Biebermann
Patrick Scheerer
Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective
Frontiers in Endocrinology
G-protein coupled receptor
melanocortin receptors
MC4R
MSH
AgRP
ACTH
author_facet Nicolas Heyder
Gunnar Kleinau
Michal Szczepek
Dennis Kwiatkowski
David Speck
Lucia Soletto
José Miguel Cerdá-Reverter
Heiko Krude
Peter Kühnen
Heike Biebermann
Patrick Scheerer
author_sort Nicolas Heyder
title Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective
title_short Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective
title_full Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective
title_fullStr Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective
title_full_unstemmed Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective
title_sort signal transduction and pathogenic modifications at the melanocortin-4 receptor: a structural perspective
publisher Frontiers Media S.A.
series Frontiers in Endocrinology
issn 1664-2392
publishDate 2019-07-01
description The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating MC4R variants are the most frequent cause of monogenic obesity. In general, obesity is a growing problem on a global scale and is of social, medical, and economic relevance. A significant goal is to develop optimized pharmacological tools targeting MC4R without adverse effects. To date, this has not been achieved because of inter alia non-selective ligands across the five functionally different MCR subtypes (MC1-5R). This motivates further investigation of (i) the three-dimensional MC4R structure, (ii) binding mechanisms of various ligands, and (iii) the molecular transfer process of signal transduction, with the aim of understanding how structural features are linked with functional-physiological aspects. Unfortunately, experimentally elucidated structural information is not yet available for the MC receptors, a group of class A G-protein coupled receptors (GPCRs). We, therefore, generated MC4R homology models and complexes with interacting partners to describe approximate structural properties associated with signaling mechanisms. In addition, molecular insights from pathogenic mutations were incorporated to discriminate more precisely their individual malfunction of the signal transfer mechanism.
topic G-protein coupled receptor
melanocortin receptors
MC4R
MSH
AgRP
ACTH
url https://www.frontiersin.org/article/10.3389/fendo.2019.00515/full
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spelling doaj-c6f24ae870f145b8a2c9a641fa877eeb2020-11-25T02:20:57ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922019-07-011010.3389/fendo.2019.00515459031Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural PerspectiveNicolas Heyder0Gunnar Kleinau1Michal Szczepek2Dennis Kwiatkowski3David Speck4Lucia Soletto5José Miguel Cerdá-Reverter6Heiko Krude7Peter Kühnen8Heike Biebermann9Patrick Scheerer10Group Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyDepartamento de Fisiología de Peces y Biotecnología, Consejo Superior de Investigaciones Científicas, Instituto de Acuicultura Torre de la Sal, Ribera de Cabanes, SpainDepartamento de Fisiología de Peces y Biotecnología, Consejo Superior de Investigaciones Científicas, Instituto de Acuicultura Torre de la Sal, Ribera de Cabanes, SpainInstitute of Experimental Pediatric Endocrinology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyInstitute of Experimental Pediatric Endocrinology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyInstitute of Experimental Pediatric Endocrinology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyThe melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating MC4R variants are the most frequent cause of monogenic obesity. In general, obesity is a growing problem on a global scale and is of social, medical, and economic relevance. A significant goal is to develop optimized pharmacological tools targeting MC4R without adverse effects. To date, this has not been achieved because of inter alia non-selective ligands across the five functionally different MCR subtypes (MC1-5R). This motivates further investigation of (i) the three-dimensional MC4R structure, (ii) binding mechanisms of various ligands, and (iii) the molecular transfer process of signal transduction, with the aim of understanding how structural features are linked with functional-physiological aspects. Unfortunately, experimentally elucidated structural information is not yet available for the MC receptors, a group of class A G-protein coupled receptors (GPCRs). We, therefore, generated MC4R homology models and complexes with interacting partners to describe approximate structural properties associated with signaling mechanisms. In addition, molecular insights from pathogenic mutations were incorporated to discriminate more precisely their individual malfunction of the signal transfer mechanism.https://www.frontiersin.org/article/10.3389/fendo.2019.00515/fullG-protein coupled receptormelanocortin receptorsMC4RMSHAgRPACTH