Abstract
The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R–Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor–Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.
Highlights
The melanocortin-4 receptor (MC4R) is one of five human melanocortin receptor subtypes (MC1−5R) that share a set of similar peptidic ligands and constitute an evolutionarily related group of class A Gsαβγ protein (Gs)-protein-coupled receptors (GPCRs)
MC4R–Gs complex formation with agonists NDP-α-melanocytestimulating hormone (α-MSH) and setmelanotide To determine the cryo-electron microscopy (cryo-EM) structure of MC4R-signaling complexes with different agonists, we used NDP-α-MSH and setmelanotide due to their clinical significance and high in vitro binding potency (Ki = 0.7 nM16 and 2.1 nM,[12] respectively) compared with α-MSH (Ki = 51 nM16) which was essential for generating stable complex samples
Here we report cryo-EM structures of active-state MC4R–Gs complexes bound to the FDA-approved peptide agonists NDP-αMSH and setmelanotide (Fig. 1)
Summary
The melanocortin-4 receptor (MC4R) is one of five human melanocortin receptor subtypes (MC1−5R) that share a set of similar peptidic ligands and constitute an evolutionarily related group of class A G-protein-coupled receptors (GPCRs). MCRs regulate energy homeostasis, pigmentation, cardiovascular function, and sexual functions.[1] In particular, the MC4R plays a central role in energy balance and appetite regulation.[2]. Naturally-occurring human MC4R mutants are the most frequent monogenic cause of obesity, with ~160 identified variants so far.[3]. Activation of MC4R by its natural agonists α-melanocytestimulating hormone (α-MSH) or β-MSH leads to appetitereducing effects. Binding of the endogenous inverse agonist agouti-related peptide (AgRP) causes orexigenic effects[4] by reducing high levels of basal signaling activity.[5]
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