The Structural Basis of Peptide Binding at Class A G Protein-Coupled Receptors
Abstract
:1. Introduction
1.1. G Protein-Coupled Receptors Are a Significant Target of Therapeutic Intervention
1.2. Peptide-Activated Receptors Are a Large Percentage of the GPCR Class A
1.3. Diversity of Peptide Ligands
1.4. Reducing the Flexibility of Peptide Ligands Is Crucial for Success in Co-Crystallization
1.5. Complexity of Peptide Ligand and Receptor Interactions
2. Comparison of Peptide Binding Modes across Class A GPCRs
2.1. Diversity in the Binding Modes of the Peptide Ligands to Class A GPCRs
2.2. Peptide Ligands Affect the Conformation of the Extracellular Surface
2.3. ECL1 and ECL2 Bound Conformation Have Conversed across Class A Peptide-GPCRs
2.4. A List of 14 Common Interacting Residues Suggests a General Peptide Recognition and Binding Mechanism among Nine Class A GPCRs
3. Structural Changes in Peptides Induced by Receptors Are Critical for Binding
3.1. Neurotensin
3.2. Apelin
3.3. Endothelin
3.4. The Complement System Peptide Ligand C5a
3.5. Ghrelin
3.6. Gonadotropin-Releasing Hormone
3.7. Neuropeptide Y
3.8. Opioid Peptides
4. Implications for Future Studies
4.1. Peptides Need to Be Characterized in Their Bound State
4.2. Mimetics of the Bound-State Conformations Can Aid in Structure Determination and Drug Discovery
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Peptide Modification | Example | Function |
---|---|---|
C-terminal amidation | Neuropeptide Y (NPY), neuromedin B | C-terminal amidation reduces the overall charge of a peptide, forms key hydrogen interactions that are important for the potency of the peptide [15], and increases the metabolic stability of peptides as well as their ability to resist enzymatic degradation [16] |
N-terminal pyroglutamic acid | Thyroid stimulating hormone (TSH), gonadotropin-releasing hormone I (GnRHI), regulated upon activation, Normal T cell expressed, and presumably secreted (RANTES)/chemokine ligand 5 (CCL5) | The pyroglutamic acid is often involved in peptide-receptor recognition and potency [17], and provides stability against N-terminal degradation [18] |
Bromination | Neuropeptides B and W (NPBW) | Bromination on N-terminal tryptophan might protect the peptide from amino-peptidases’ degradation [19] |
Lipidation | Ghrelin | The attached lipid group (e.g., octanoyl group) is essential to the activity of the peptide [19] and affects the hydrophobicity of the peptide [20] |
Disulfide bridge formation | Endothelin, vasopressin | The disulfide bonds stabilize the defined secondary structure [21], stabilizing the bound conformation of the peptide [22] |
Differential proteolysis | Bradykinin, angiotensin, NPY/NPY3-36, apelin (Ape)-13/Ape-17/Ape 36, adrenocorticotropic hormone (ACTH), pro-opiomelanocortin (POMC) cleavage yielding α-, β-, and γ- melanocyte-stimulating hormone (MSH), and endorphins | Proteolysis can switch the activity of the peptides on and off [23] or differentiates the binding selectivity and the biological responses of the peptides [24] |
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Vu, O.; Bender, B.J.; Pankewitz, L.; Huster, D.; Beck-Sickinger, A.G.; Meiler, J. The Structural Basis of Peptide Binding at Class A G Protein-Coupled Receptors. Molecules 2022, 27, 210. https://doi.org/10.3390/molecules27010210
Vu O, Bender BJ, Pankewitz L, Huster D, Beck-Sickinger AG, Meiler J. The Structural Basis of Peptide Binding at Class A G Protein-Coupled Receptors. Molecules. 2022; 27(1):210. https://doi.org/10.3390/molecules27010210
Chicago/Turabian StyleVu, Oanh, Brian Joseph Bender, Lisa Pankewitz, Daniel Huster, Annette G. Beck-Sickinger, and Jens Meiler. 2022. "The Structural Basis of Peptide Binding at Class A G Protein-Coupled Receptors" Molecules 27, no. 1: 210. https://doi.org/10.3390/molecules27010210