Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R
Abstract
1. Introduction
2. Results and Discussion
2.1. Distinct Binding Mode Led to Unique Signaling
2.2. Structural Dynamics of GLP-1R for Ligand-Bound and Ligand-Free Conditions
2.3. Structural Plasticity of GLP-1R in the Holo State
2.4. Binding Pocket Variants upon Danuglipron, CHU-128, and Peptide 19 Binding
2.5. Signal Transduction Associated with Distinct Types of Ligand Binding
2.5.1. Ligand Recognition and Binding via the Extracellular Domain
2.5.2. Signal Transduction Along the Transmembrane Domain
2.5.3. Features of the Intracellular Binding Domain
2.6. Biased Agonism and Receptor Signaling Mechanisms
2.6.1. Inferring β-Arrestin-Bound to GLP-1R via Structural Comparison with Related Class B1 GPCRs
2.6.2. Promising Pharmacokinetics of Biased Agonists
3. Materials and Methods
3.1. Complex Structure Preparation
3.2. Molecular Dynamics Simulation Protocol
3.3. Analysis of Simulated Structures
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Compounds | Danuglipron | CHU-128 | Peptide 19 |
---|---|---|---|
Chemical structure | Y1AEGTFTSDYSIY LDKQAAAEFVNW LLAGGPSAPPPSK38 | ||
Molecular mass | 555.6 g/mol | 883.96 g/mol | 4064 g/mol |
Ligand type | Small molecule | Small molecule | 38-residue peptide |
Activity type | Balanced | G protein-biased | Balanced |
Binding site | Orthosteric | Orthosteric | Orthosteric |
PDB | Simulation Time | Replicates | Resolution (Å) | Activity State | Ligand | Ligand Type | Downstream Protein |
---|---|---|---|---|---|---|---|
6X1A | 500 ns | 3 | 2.50 | Active | Danuglipron | Balanced agonist | Gs |
6X19 | 500 ns | 3 | 2.10 | Active | CHU-128 | Biased agonist | Gs |
7RTB | 500 ns | 3 | 2.14 | Active | Peptide 19 | Balanced agonist | Gs |
7RTB | 500 ns | 3 | 2.14 | Ligand-Free | - | - | - |
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Xu, M.; Vogel, H.; Yuan, S. Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R. Molecules 2025, 30, 3216. https://doi.org/10.3390/molecules30153216
Xu M, Vogel H, Yuan S. Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R. Molecules. 2025; 30(15):3216. https://doi.org/10.3390/molecules30153216
Chicago/Turabian StyleXu, Marc, Horst Vogel, and Shuguang Yuan. 2025. "Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R" Molecules 30, no. 15: 3216. https://doi.org/10.3390/molecules30153216
APA StyleXu, M., Vogel, H., & Yuan, S. (2025). Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R. Molecules, 30(15), 3216. https://doi.org/10.3390/molecules30153216