Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 Oct 2024
01 Oct 2024
Historique:
received:
21
09
2023
accepted:
23
07
2024
medline:
2
10
2024
pubmed:
2
10
2024
entrez:
1
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39353917
doi: 10.1038/s41467-024-50827-7
pii: 10.1038/s41467-024-50827-7
doi:
Substances chimiques
Receptor, Melanocortin, Type 4
0
Single-Domain Antibodies
0
MC4R protein, human
0
alpha-MSH
581-05-5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7029Subventions
Organisme : Agentschap Innoveren en Ondernemen (Flanders Innovation & Entrepreneurship)
ID : HBC_2020.2042
Informations de copyright
© 2024. The Author(s).
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