ArticleNature communications2024
Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed.
- Realizing the potential of agonistic antibody immunotherapy.Nature reviews. Drug discovery · 2026Review
- Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders.Acta pharmaceutica Sinica. B · 2026Review
- De novo design of miniproteins targeting GPCRs.Nature · 2026Article
- Nanobodies unlock new mechanisms to target G protein-coupled receptors.Molecular pharmacology · 2026Review
- Article
- Advances in Therapeutic Antibody Discovery and Development Targeting G Protein-Coupled Receptors.Pharmacology research & perspectives · 2026Review
- Extracellular nanobody screening using conformationally stable GPCR variants.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Development of bitopic nanobody-ligand conjugates targeting G protein-coupled receptors and exhibiting logic-gated signaling.PLoS biology · 2025Article
- Resolution Pharmacology: State-of-the-art and therapeutic landscape.Pharmacological reviews · 2025Review
- Progress toward new function and design of extracellular G protein-coupled receptor nanobodies.Molecular pharmacology · 2025Review
- Article
- Epitope-directed selection of GPCR nanobody ligands with evolvable function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Nanobody-based conjugates targeting small molecule-binding GPCRs and exhibiting logic-gated signaling.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
22 authors.
Funding
Abstract
The melanocortin receptor 4 (MC4R) belongs to the melanocortin receptor family of G-protein coupled receptors and is a key switch in the leptin-melanocortin molecular axis that controls hunger and satiety. Brain-produced hormones such as α-melanocyte-stimulating hormone (agonist) and agouti-related peptide (inverse agonist) regulate the molecular communication of the MC4R axis but are promiscuous for melanocortin receptor subtypes and induce a wide array of biological effects. Here, we use a chimeric construct of conformation-selective, nanobody-based binding domain (a ConfoBody Cb80) and active state-stabilized MC4R-β2AR hybrid for efficient de novo discovery of a sequence diverse panel of MC4R-specific, potent and full agonistic nanobodies. We solve the active state MC4R structure in complex with the full agonistic nanobody pN162 at 3.4 Å resolution. The structure shows a distinct interaction with pN162 binding deeply in the orthosteric pocket. MC4R peptide agonists, such as the marketed setmelanotide, lack receptor selectivity and show off-target effects. In contrast, the agonistic nanobody is highly specific and hence can be a more suitable agent for anti-obesity therapeutic intervention via MC4R.
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Registered trials
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.