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TitleStructure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 7029, Year 2024
Publish dateOct 1, 2024
AuthorsThomas Fontaine / Andreas Busch / Toon Laeremans / Stéphane De Cesco / Yi-Lynn Liang / Veli-Pekka Jaakola / Zara Sands / Sarah Triest / Simonas Masiulis / Lies Dekeyzer / Noor Samyn / Nicolas Loeys / Lisa Perneel / Melanie Debaere / Murielle Martini / Charlotte Vantieghem / Richa Virmani / Kamila Skieterska / Stephanie Staelens / Rosa Barroco / Maarten Van Roy / Christel Menet /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:39353917 / PubMed Central
MethodsEM (single particle)
Resolution3.4 Å
Structure data

18442

8qj2

EMDB-18442, PDB-8qj2:
Structure of active state MC4R in complex with a potent ligand mimicking nanobody
Method: EM (single particle) / Resolution: 3.4 Å

Source
  • homo sapiens (human)
  • lama glama (llama)
  • discosoma sp. (sea anemone)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / GPCR / ConfoBody / agonistic nanobody

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