Abstract
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.
Highlights
The melanocyte-stimulating hormones (α, β, γ-MSH) and the adrenocorticotropic hormone (ACTH) are agonistic peptidic ligands that bind to a group of five class A G-protein coupled receptors (GPCRs) [1], namely the melanocortin-receptors 1–5 (MC1-5R)
The melanocortin-4 receptor (MC4R) is constituted by structural features typical for GPCRs such as seven transmembrane spanning helices connected by intra- and extracellular loops, an extracellular N-terminus, and an intracellular C-terminal tail [76]
The MC4R is characterized by a regular α-helical conformation of TMH5 because of a methionine instead of a proline (P5.50) that is highly conserved in class A GPCRs and induces a helical kink and bulge
Summary
The melanocyte-stimulating hormones (α-, β-, γ-MSH) and the adrenocorticotropic hormone (ACTH) are agonistic peptidic ligands that bind to a group of five class A GPCRs [1], namely the melanocortin-receptors 1–5 (MC1-5R). The endogenous melanocortin receptor antagonist AgRP [2,3,4] inhibits basal constitutive signaling [5] as a potential inverse agonist and simultaneously prevents MSH binding. These ligands and receptors are involved in regulating various physiological functions, such as skin pigmentation, energy homeostasis, erythrocyte differentiation, thermal homeostasis, appetite, and adrenal, or sexual function [6,7,8,9]. The MC2R, in contrast to other MCRs, is specific because it is activated only by ACTH and requires an interplay with the melanocortin receptor accessory protein (MRAP) to attain functional expression [11]. MC2R activation is associated with stress responses by promoting the synthesis and secretion of adrenal glucocorticoids along the hypothalamic-pituitaryadrenal axis [12]
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