Toward Atomic-Scale Understanding of Ligand Recognition in the Muscle Nicotinic Receptor

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Abstract:

The nicotinic receptor at the motor endplate has served as a prototype for understanding structure,function and ligand recognition in the superfamily of pentameric ligand-gated ion channels.Yet despite this advanced state of knowledge, atomic-scale understanding of such elementary processes as ligand recognition has remained elusive owing to the lack of a high-resolution x-ray structure.However,the field has recently entered a state of rapid advancement following the discovery and atomic structural determination of the water-soluble acetylcholine binding protein (AChBP),a homolog of the receptor ligand binding domain.The AChBP structure provides the theoretical foundation for generating homology models of the corresponding receptor ligand binding domains within this structural family of receptors.Experimental assignment of residue equivalence between AChBP and receptor subunits subsequently yielded homology models ready for experimental testing.One such test is computational determination of ligand docking orientation in conjunction with mutagenesis of predicted contact residues and measurements of ligand binding affinity.Applied to different analogs of the competitive antagonist curare,docking computations that incorporate intrinsic protein flexibility reveal fundamentally distinct orientations of each analog bound to AChBP.The different contact residues predicted for each analog were tested and confirmed by mutagenesis of AChBP followed by measurements of ligand binding.By applying the same computational and experimental approaches to the adult human muscle AChR,we find that the two curare analogs also dock in distinctly different orientations.Thus subtle structural changes in the ligand,and by extension,structural differences in non-conserved residues among receptor subtypes and species,can dramatically alter the orientation of the bound ligand.The results have important implications for design of drugs targeting nicotinic receptors and members of the superfamily of pentameric ligand-gated ion channels.

Keywords: acetylcholine receptor and binding protein; curariform antagonists; flexible ligand docking; mutagenesis-based homology model

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867043455855

Affiliations: Receptor Biology Laboratory,Department of Physiology and Biophysics,Mayo Clinic College of Medicine,Rochester,Minnesota 55905,USA.

Publication date: March 1, 2004

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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