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Curariform antagonists bind in different orientations to acetylcholine-binding protein.
Fan Gao1, Nina Bern, Alicia Little
1Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Clinic Department of Pharmacology, Mayo Graduate School, Rochester, Minnesota 55905, USA.
The Journal of Biological Chemistry
|April 19, 2003
Summary
Structurally similar drugs, d-tubocurarine and metocurine, bind differently to acetylcholine-binding protein (AChBP). This study reveals distinct ligand orientations, impacting drug design and structure-activity relationship interpretation for nicotinic acetylcholine receptors (AChRs).
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Acetylcholine-binding protein (AChBP) serves as a model for nicotinic acetylcholine receptor (AChR) ligand-binding domains.
- Understanding competitive antagonist interactions at an atomic level is crucial for drug development.
Purpose of the Study:
- To investigate the atomic-level interactions of curare derivatives, d-tubocurarine (d-TC) and metocurine, with AChBP.
- To elucidate the binding orientations and structural basis of their interactions.
Main Methods:
- Computational methods including molecular dynamics simulations and molecular docking.
- Site-directed mutagenesis of AChBP binding site residues.
- Ligand binding measurements.
Main Results:
- Molecular dynamics simulations predicted distinct docking orientations for d-TC and metocurine within the AChBP binding pocket.
- Mutagenesis and binding assays confirmed these differing orientations, revealing specific residue interactions unique to each ligand.
- The curare scaffold exhibited approximately 170-degree rotation and 30-degree tilt differences between the two ligands.
Conclusions:
- Structurally similar ligands can adopt fundamentally different orientations within receptor binding sites.
- These distinct binding modes present challenges for interpreting structure-activity relationships (SAR) in drug discovery.
- The findings highlight the complexity of ligand-receptor interactions and the need for detailed structural analysis.