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Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.
Lu, Jun; Byrne, Noel; Wang, John; Bricogne, Gerard; Brown, Frank K; Chobanian, Harry R; Colletti, Steven L; Di Salvo, Jerry; Thomas-Fowlkes, Brande; Guo, Yan; Hall, Dawn L; Hadix, Jennifer; Hastings, Nicholas B; Hermes, Jeffrey D; Ho, Thu; Howard, Andrew D; Josien, Hubert; Kornienko, Maria; Lumb, Kevin J; Miller, Michael W; Patel, Sangita B; Pio, Barbara; Plummer, Christopher W; Sherborne, Bradley S; Sheth, Payal; Souza, Sarah; Tummala, Srivanya; Vonrhein, Clemens; Webb, Maria; Allen, Samantha J; Johnston, Jennifer M; Weinglass, Adam B; Sharma, Sujata; Soisson, Stephen M.
Afiliación
  • Lu J; Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Byrne N; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Wang J; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Bricogne G; Global Phasing Limited, Cambridge, UK.
  • Brown FK; Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Chobanian HR; Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Colletti SL; Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Di Salvo J; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Thomas-Fowlkes B; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Guo Y; Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Hall DL; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Hadix J; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Hastings NB; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Hermes JD; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Ho T; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Howard AD; Department of Cardiometabolic Disease, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Josien H; Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Kornienko M; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Lumb KJ; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Miller MW; Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Patel SB; Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Pio B; Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Plummer CW; Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Sherborne BS; Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Sheth P; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Souza S; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Tummala S; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Vonrhein C; Global Phasing Limited, Cambridge, UK.
  • Webb M; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Allen SJ; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Johnston JM; Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Weinglass AB; Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Sharma S; Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
  • Soisson SM; Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
Nat Struct Mol Biol ; 24(7): 570-577, 2017 Jul.
Article en En | MEDLINE | ID: mdl-28581512
Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores Acoplados a Proteínas G Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2017 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Receptores Acoplados a Proteínas G Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2017 Tipo del documento: Article