Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist

Thomas 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 and Christel Menet ()
Additional contact information
Thomas Fontaine: Confo Therapeutics N.V
Andreas Busch: Confo Therapeutics N.V
Toon Laeremans: Confo Therapeutics N.V
Stéphane De Cesco: Confo Therapeutics N.V
Yi-Lynn Liang: Confo Therapeutics N.V
Veli-Pekka Jaakola: Confo Therapeutics N.V
Zara Sands: Confo Therapeutics N.V
Sarah Triest: Confo Therapeutics N.V
Simonas Masiulis: Materials and Structural Analysis, Thermo Fisher Scientific
Lies Dekeyzer: Confo Therapeutics N.V
Noor Samyn: Confo Therapeutics N.V
Nicolas Loeys: Confo Therapeutics N.V
Lisa Perneel: Confo Therapeutics N.V
Melanie Debaere: Confo Therapeutics N.V
Murielle Martini: Confo Therapeutics N.V
Charlotte Vantieghem: Confo Therapeutics N.V
Richa Virmani: Confo Therapeutics N.V
Kamila Skieterska: Confo Therapeutics N.V
Stephanie Staelens: Confo Therapeutics N.V
Rosa Barroco: Confo Therapeutics N.V
Maarten Van Roy: Confo Therapeutics N.V
Christel Menet: Confo Therapeutics N.V

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50827-7

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