British journal of pharmacologyJul 24, 2010

A specific hydrogen bond in exendin-4 mainly explains its stronger binding to the rat GLP-1 receptor’s front region compared to GLP-1

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Updated Apr 3, 2026

Abstract

The membrane-tethered N-terminal domain of human GLP-1 receptor binds GLP-1 and Exendin-4 with similar affinity.

GLP-1 and Exendin-4 display contrasting affinities when bound to the isolated N-terminal domain compared to the membrane-tethered domain.
The selectivity of Exendin-4 variants was influenced by specific amino acids, such as Ser-32 in the ligand.
Mutating Glu-68 in human GLP-1 receptor to Asp restored the selectivity for Exendin-4 observed in the rat receptor.
The findings suggest that structural differences at the receptor level may impact drug affinity and selectivity.

Simplified

BACKGROUND AND PURPOSE: Exendin-4 (exenatide, Ex4) is a high-affinity peptide agonist at the glucagon-like peptide-1 receptor (GLP-1R), which has been approved as a treatment for type 2 diabetes. Part of the drug/hormone binding site was described in the crystal structures of both GLP-1 and Ex4 bound to the isolated N-terminal domain (NTD) of GLP-1R. However, these structures do not account for the large difference in affinity between GLP-1 and Ex4 at this isolated domain, or for the published role of the C-terminal extension of Ex4. Our aim was to clarify the pharmacology of GLP-1R in the context of these new structural data.

EXPERIMENTAL APPROACH: The affinities of GLP-1, Ex4 and various analogues were measured at human and rat GLP-1R (hGLP-1R and rGLP-1R, respectively) and various receptor variants. Molecular dynamics coupled with in silico mutagenesis were used to model and interpret the data.

KEY RESULTS: The membrane-tethered NTD of hGLP-1R displayed similar affinity for GLP-1 and Ex4 in sharp contrast to previous studies using the soluble isolated domain. The selectivity at rGLP-1R for Ex4(9-39) over Ex4(9-30) was due to Ser-32 in the ligand. While this selectivity was not observed at hGLP-1R, it was regained when Glu-68 of hGLP-1R was mutated to Asp.

CONCLUSIONS AND IMPLICATIONS: GLP-1 and Ex4 bind to the NTD of hGLP-1R with similar affinity. A hydrogen bond between Ser32 of Ex4 and Asp-68 of rGLP-1R, which is not formed with Glu-68 of hGLP-1R, is responsible for the improved affinity of Ex4 at the rat receptor.

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A specific hydrogen bond in exendin-4 mainly explains its stronger binding to the rat GLP-1 receptor’s front region compared to GLP-1

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