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Study · Not a test of the peptide alone · 2021

3 results

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.

Cong Z, Chen LN, Ma H, Zhou Q, Zou X, Ye C, Dai A, Liu Q, Liu Q, Huang W, Sun X, Wang X and 8 more

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Xu P, Zhao L, Xia T, Zhong W, Yang D, Eric Xu H, Zhang Y, Wang MW

Nature communications18 Jun 2021Cited by 79 (Europe PMC)

PMID34145245 (opens in a new tab)PMCIDPMC8213797 (opens in a new tab)DOI10.1038/s41467-021-24058-z (opens in a new tab)PepBankPUB-34145245
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Summary

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone3

In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Orforglipron.

  1. 01LabNot a test of Orforglipron aloneIn vitro (cell-free)Mechanism

    In human GLP-1R structures including the LY3502970 complex, compound 2 bound C347 and triggered outward TM6 movement with the extracellular domain.

    In plain wordsIn lab tests of receptor complexes including orforglipron, compound 2 bound the receptor and moved a receptor helix outward.

    Peptide
    Orforglipron
    Outcome
    Not applicableCompound 2 covalent binding and receptor movement
    Study

    n: not reported in source

    Human GLP-1R complexes
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site.
    1 context sentence
    Summary · context
    Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  2. 02LabNot a test of Orforglipron aloneIn vitro (cell-free)Mechanism

    In human GLP-1R complexes including LY3502970, compound 2 enhanced agonist binding through positive allosteric modulation.

    In plain wordsIn lab tests of receptor complexes including orforglipron, compound 2 enhanced agonist binding.

    Peptide
    Orforglipron
    Outcome
    IncreaseAgonist binding enhancement
    Study

    n: not reported in source

    Human GLP-1R complexes
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling.
    1 context sentence
    Summary · context
    Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  3. 03LabNot a test of Orforglipron aloneIn vitro (cell-free)Mechanism

    In human GLP-1R complexes including LY3502970, compound 2 enhanced G protein coupling through positive allosteric modulation.

    In plain wordsIn lab tests of receptor complexes including orforglipron, compound 2 enhanced G protein coupling.

    Peptide
    Orforglipron
    Outcome
    IncreaseG protein coupling enhancement
    Study

    n: not reported in source

    Human GLP-1R complexes
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling.
    1 context sentence
    Summary · context
    Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 3Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 2

    14 Oct 2026, 01:46 UTC

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:06 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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