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

Author:

Menet Christel1ORCID,Laeremans Toon1,Fontaine Thomas1,Busch Andreas1,De Cesco Stéphane1,Triest Sarah2,Dekeyzer Lies1,Samyn Noor1,Loeys Nicolas1,Perneel Lisa1,Debaere Melanie1,virmani richa1,skieterska kamila1,staelens stephanie1,Roy maarten Van1,Liang Yi-Lynn3,Jaakola Veli-Pekka4ORCID,Sands Zara5,Masiulis Simonas6,Martini Murielle1,Barroco Rosa7

Affiliation:

1. Confo Therapeutics

2. VIB-VUB center for Structural Biology

3. Monash University

4. LeadXpro AG

5. Eli Lilly and Company

6. Thermo Fisher Scientific

7. Inari Agriculture

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. Using a conformation-selective ConfoBody, the use of active state-stabilized MC4R facilitated efficient de novo discovery of a sequence diverse panel of MC4R-specific, potent and full agonistic nanobodies. We solved the active state MC4R structure in complex with the full agonistic nanobody pN162 at 3.4 Å resolution. The structure shows a unique interaction with pN162 binding deeply in the orthosteric pocket of MC4R and lacking the structural interactions of MC4R agonists reported to date. 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.

Publisher

Research Square Platform LLC

Reference51 articles.

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3. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity;Lotta LA;Cell,2019

4. The cloning of a family of genes that encode the melanocortin receptors;Mountjoy KG;Science,1992

5. Maaser, C. et al. Role of the melanocortin system in inflammation. Ann. N. Y. Acad. Sci. 2006, 1072, 123–134 (2006).

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