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Area of Science:

  • Structural Biology
  • Pharmacology
  • Biochemistry

Background:

  • Free fatty acid receptor 1 (GPR40) plays a crucial role in metabolic regulation.
  • Synthetic agonists activate GPR40 via distinct allosteric sites, influencing receptor function differently.
  • Previous studies identified an allosteric site for partial agonists like TAK-875.

Purpose of the Study:

  • To determine the crystal structure of human GPR40 bound to a synthetic full agonist.
  • To elucidate the binding mode and mechanism of action of a novel GPR40 full agonist.
  • To investigate the potential of this site for endogenous free fatty acid (FFA) binding.

Main Methods:

  • X-ray crystallography to determine the 2.76-Å crystal structure of human GPR40 complexed with compound 1.
  • Biochemical assays to characterize the G protein coupling (Gαq and Gαs) of compound 1.
  • Computational modeling to assess the binding of endogenous FFA, γ-linolenic acid.

Main Results:

  • The crystal structure revealed compound 1 binding to a second, distinct allosteric site near intracellular loop 2 (ICL2).
  • Compound 1 functions as a dual Gαq and Gαs-coupled full agonist, unlike the Gαq-specific partial agonist TAK-875.
  • Ligand binding stabilizes ICL2, likely enhancing G protein activation; γ-linolenic acid and compound 1 show positive cooperativity with TAK-875.

Conclusions:

  • A second allosteric site on GPR40 accommodates full agonists, leading to distinct G protein coupling profiles.
  • Stabilization of ICL2 by ligands is a key mechanism for modulating G protein activity at GPR40.
  • The identified allosteric site may also serve as a binding pocket for endogenous free fatty acids.