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Glucagon-like Receptor Agonists01:24

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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells
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Full-length human GLP-1 receptor structure without orthosteric ligands.

Fan Wu1,2,3, Linlin Yang4, Kaini Hang1,2,3

  • 1iHuman Institute, ShanghaiTech University, Shanghai, China.

Nature Communications
|March 11, 2020
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Summary

We determined the inactive structure of the glucagon-like peptide-1 receptor (GLP-1R) without its peptide ligand, revealing a unique closed extracellular domain. This finding offers new insights into GLP-1R activation for diabetes treatment.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor crucial for glucose homeostasis and type 2 diabetes treatment.
  • Previous studies revealed structures of GLP-1R with agonists, but its extracellular domain (ECD) conformation without ligands remained largely unknown, hindering understanding of receptor activation.

Purpose of the Study:

  • To determine the peptide-free crystal structure of the full-length human GLP-1R in an inactive state.
  • To investigate the conformational dynamics of the GLP-1R ECD in the absence of orthosteric ligands.

Main Methods:

  • X-ray crystallography at 3.2 Å resolution to obtain the peptide-free GLP-1R structure.
  • Disulfide cross-linking to validate the physiological relevance of observed conformations.
  • Electron microscopy (EM) and molecular dynamics (MD) simulations to explore ECD conformational dynamics.

Main Results:

  • The study reports the first 3.2 Å resolution, peptide-free crystal structure of full-length human GLP-1R in an inactive state.
  • The structure reveals a unique closed conformation of the GLP-1R extracellular domain (ECD).
  • Disulfide cross-linking, EM, and MD simulations confirm the physiological relevance and dynamic nature of the ECD, essential for GLP-1 binding.

Conclusions:

  • The determined inactive structure provides a crucial snapshot of the peptide-free GLP-1R.
  • The findings offer significant insights into the activation pathway of GLP-1R and the broader class B G protein-coupled receptor family.
  • Understanding the inactive conformation and dynamics is key to developing novel therapeutics for type 2 diabetes.