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

Frontiers in Endocrinology

Lucia Soletto¹  José Miguel Cerdá-Reverter¹  Patrick Scheerer²  Nicolas Heyder²  David Speck²  Gunnar Kleinau²  Michal Szczepek²  Dennis Kwiatkowski²  Heike Biebermann³  Peter Kühnen³  Heiko Krude³ 

[1] Departamento de Fisiología de Peces y Biotecnología, Consejo Superior de Investigaciones Científicas, Instituto de Acuicultura Torre de la Sal, Ribera de Cabanes, Spain;Group 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, Germany;Institute of Experimental Pediatric Endocrinology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany;

关键词: G-protein coupled receptor;    melanocortin receptors;    MC4R;    MSH;    AgRP;    ACTH;   

DOI  :  10.3389/fendo.2019.00515

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown