ArticleCell research2021
Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.
Article in Cell research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed.
- Advances in Cyclic Peptides Targeting G Protein-Coupled Receptors.Chembiochem : a European journal of chemical biology · 2026Review
- Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders.Acta pharmaceutica Sinica. B · 2026Review
- The Synthetic Melanocortin Agonist NDP-MSH Ameliorates THSD7A-Associated Membranous Nephropathy in an Active Immunization Mouse Model.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Ultrarapid MC1R protein and associated plumage color evolution in the domestic chicken.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Neural Melanocortin Receptors in Fish: Insights into Growth Regulation and Aquaculture Advancement.Biomolecules · 2026Review
- A progressive fine-tuning framework with dynamic parameter selection for low-resource peptide-GPCR interaction prediction.Briefings in bioinformatics · 2026Article
- The role of accessory proteins and co-factors in regulation of melanocortin-4 receptor signalling: An update.Journal of neuroendocrinology · 2026Review
- GPCR Heterodimers: Implications for Biased Signaling.Handbook of experimental pharmacology · 2026Review
- Review
- Elucidating biased signaling in class A GPCRs.Trends in pharmacological sciences · 2025Review
- Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.Nature medicine · 2025Article
- A peptide display system identifies a potent mutant β-melanocyte-stimulating hormone agonist of melanocortin-4 receptor.Cell genomics · 2025Article
- IMPROVE 2023: The 2nd International Meeting on Pathway-Related Obesity: Vision & Evidence.Clinical obesity · 2025Article
- MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor.Nature communications · 2025Article
- The Novel Achievements in Oncological Metabolic Radio-Therapy: Isotope Technologies, Targeted Theranostics, Translational Oncology Research.Medical sciences (Basel, Switzerland) · 2025Review
- MIC: A deep learning tool for assigning ions and waters in cryo-EM and crystal structures.Nature communications · 2025Article
- Article
- Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways.Human molecular genetics · 2025Article
- N-Branched Tricyclic Guanidines as Novel Melanocortin-3 Receptor Agonists and Melanocortin-4 Receptor Antagonists.Journal of medicinal chemistry · 2025Article
- Pro-Opiomelanocortin and Melanocortin Receptor 3 and 4 Mutations in Genetic Obesity.Biomolecules · 2025Review
Corrections and comments
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Authors and funding
22 authors.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.