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Structure paper

TitleStructural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 20, Page e2200155119, Year 2022
Publish dateMay 17, 2022
AuthorsZhaotong Cong / Qingtong Zhou / Yang Li / Li-Nan Chen / Zi-Chen Zhang / Anyi Liang / Qing Liu / Xiaoyan Wu / Antao Dai / Tian Xia / Wei Wu / Yan Zhang / Dehua Yang / Ming-Wei Wang /
PubMed AbstractGlucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require ...Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R.
External linksProc Natl Acad Sci U S A / PubMed:35561211 / PubMed Central
MethodsEM (single particle)
Resolution2.61 - 3.09 Å
Structure data

33057

7x8r

EMDB-33057, PDB-7x8r:
Cryo-EM structure of the Boc5-bound hGLP-1R-Gs complex
Method: EM (single particle) / Resolution: 2.61 Å

33058

7x8s

EMDB-33058, PDB-7x8s:
Cryo-EM structure of the WB4-24-bound hGLP-1R-Gs complex
Method: EM (single particle) / Resolution: 3.09 Å

Chemicals

ChemComp-BYI:
2,4-bis(3-methoxy-4-thiophen-2-ylcarbonyloxy-phenyl)-1,3-bis[[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]carbonylamino]cyclobutane-1,3-dicarboxylic acid

ChemComp-WB2:
2,4-bis(3-methoxy-4-thiophen-2-ylcarbonyloxy-phenyl)-1,3-bis[[4-(2-methylpropanoylamino)phenyl]carbonylamino]cyclobutane-1,3-dicarboxylic acid

Source
  • homo sapiens (human)
  • bos taurus (cattle)
  • rattus norvegicus (Norway rat)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / glucagon-like peptide-1 receptor / type 2 diabetes mellitus / peptidomimetic agonism

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