8QJ2

Structure of active state MC4R in complex with a potent ligand mimicking nanobody

Summary for 8QJ2

• Entry DOI: 10.2210/pdb8qj2/pdb
• EMDB information: 18442
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, confobody, agonistic nanobody, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 201915.68

Authors

Busch, A.,Jaakola, V.-P.,Masiulis, S. (deposition date: 2023-09-12, release date: 2024-09-25, Last modification date: 2025-04-23)

Primary citation

Fontaine, T.,Busch, A.,Laeremans, T.,De Cesco, S.,Liang, Y.L.,Jaakola, V.P.,Sands, Z.,Triest, S.,Masiulis, S.,Dekeyzer, L.,Samyn, N.,Loeys, N.,Perneel, L.,Debaere, M.,Martini, M.,Vantieghem, C.,Virmani, R.,Skieterska, K.,Staelens, S.,Barroco, R.,Van Roy, M.,Menet, C.
Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist.
Nat Commun, 15:7029-7029, 2024

PubMed 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.

PubMed: 39353917
DOI: 10.1038/s41467-024-50827-7

Experimental method

ELECTRON MICROSCOPY (3.4 Å)