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A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification.
Nolte, Whitney M; Fortin, Jean-Philippe; Stevens, Benjamin D; Aspnes, Gary E; Griffith, David A; Hoth, Lise R; Ruggeri, Roger B; Mathiowetz, Alan M; Limberakis, Chris; Hepworth, David; Carpino, Philip A.
Afiliación
  • Nolte WM; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
  • Fortin JP; Cardiovascular and Metabolic Diseases Research Unit, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
  • Stevens BD; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
  • Aspnes GE; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.
  • Griffith DA; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
  • Hoth LR; Structural Biology and Biophysics Group, Center for Chemistry Innovation and Excellence, Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.
  • Ruggeri RB; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
  • Mathiowetz AM; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
  • Limberakis C; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.
  • Hepworth D; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
  • Carpino PA; Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
Nat Chem Biol ; 10(8): 629-31, 2014 Aug.
Article en En | MEDLINE | ID: mdl-24997604
ABSTRACT
We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro-3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Receptores de Glucagón Límite: Animals / Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Receptores de Glucagón Límite: Animals / Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos