Your browser doesn't support javascript.
loading
Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist.
Fontaine, Thomas; Busch, Andreas; Laeremans, Toon; De Cesco, Stéphane; Liang, Yi-Lynn; Jaakola, Veli-Pekka; Sands, Zara; Triest, Sarah; Masiulis, Simonas; Dekeyzer, Lies; Samyn, Noor; Loeys, Nicolas; Perneel, Lisa; Debaere, Melanie; Martini, Murielle; Vantieghem, Charlotte; Virmani, Richa; Skieterska, Kamila; Staelens, Stephanie; Barroco, Rosa; Van Roy, Maarten; Menet, Christel.
Afiliação
  • Fontaine T; Confo Therapeutics N.V, Ghent, Belgium.
  • Busch A; Confo Therapeutics N.V, Ghent, Belgium.
  • Laeremans T; Confo Therapeutics N.V, Ghent, Belgium.
  • De Cesco S; Confo Therapeutics N.V, Ghent, Belgium.
  • Liang YL; Confo Therapeutics N.V, Ghent, Belgium.
  • Jaakola VP; Confo Therapeutics N.V, Ghent, Belgium.
  • Sands Z; Confo Therapeutics N.V, Ghent, Belgium.
  • Triest S; Confo Therapeutics N.V, Ghent, Belgium.
  • Masiulis S; Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, The Netherlands.
  • Dekeyzer L; Confo Therapeutics N.V, Ghent, Belgium.
  • Samyn N; Confo Therapeutics N.V, Ghent, Belgium.
  • Loeys N; Confo Therapeutics N.V, Ghent, Belgium.
  • Perneel L; Confo Therapeutics N.V, Ghent, Belgium.
  • Debaere M; Confo Therapeutics N.V, Ghent, Belgium.
  • Martini M; Confo Therapeutics N.V, Ghent, Belgium.
  • Vantieghem C; Confo Therapeutics N.V, Ghent, Belgium.
  • Virmani R; Confo Therapeutics N.V, Ghent, Belgium.
  • Skieterska K; Confo Therapeutics N.V, Ghent, Belgium.
  • Staelens S; Confo Therapeutics N.V, Ghent, Belgium.
  • Barroco R; Confo Therapeutics N.V, Ghent, Belgium.
  • Van Roy M; Confo Therapeutics N.V, Ghent, Belgium.
  • Menet C; Confo Therapeutics N.V, Ghent, Belgium. christel.menet@confotherapeutics.com.
Nat Commun ; 15(1): 7029, 2024 Oct 01.
Article em En | MEDLINE | ID: mdl-39353917
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-ß2AR 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.
Assuntos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor Tipo 4 de Melanocortina / Anticorpos de Domínio Único Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Bélgica País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor Tipo 4 de Melanocortina / Anticorpos de Domínio Único Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Bélgica País de publicação: Reino Unido