4.6 Article

Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

期刊

ACS CHEMICAL BIOLOGY
卷 16, 期 11, 页码 2444-2452

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acschembio.1c00552

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资金

  1. National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program [2018ZX09735-001, 2018ZX09711002-002-003, 2018ZX09711002-002-005]
  2. National Natural Science Foundation [81872915, 82073904, 81620108027, 21632008, 21877118, 81773792, 81973373, 82121005]
  3. Youth Innovation Promotion Association of CAS [2018319]
  4. National Key Research and Development Program of China [2018YFA0508100]
  5. China Postdoctoral Science Foundation [2017M622365]
  6. Fundamental Research Funds for the Central Universities
  7. ECNU

向作者/读者索取更多资源

The study discovered small-molecule positive allosteric modulators (PAMs) of GLP-1R with distinct chemotypes that bind to a cryptic pocket formed by TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies revealed that PAMs enlarge the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles, providing insights into fine-tuning GLP-1R via this allosteric pocket.
The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.

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