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. 1997 Jul;73(1):52–66. doi: 10.1016/S0006-3495(97)78047-0

A model of the nicotinic receptor extracellular domain based on sequence identity and residue location.

I Tsigelny 1, N Sugiyama 1, S M Sine 1, P Taylor 1
PMCID: PMC1180908  PMID: 9199771

Abstract

We have modeled the extracellular domains of individual subunits (amino acids 31-200) in the nicotinic acetylcholine receptor using sequence homology with copper binding proteins of known crystal structure, plastocyanin and pseudoazurin, and data from recent site-specific mutagenesis, antibody mapping, and site-directed labelling studies. These data formed an initial model that was refined using molecular dynamics and mechanics as well as electrostatic and solvation energy calculations. The sequences between residues 31 and 164 in the alpha 1-subunit and corresponding residues in homologous receptor subunits show similarity with the core sequence of the cation binding site in plastocyanin and pseudoazurin, a region in the template proteins characterized by multiple hairpin loops. In addition to defining the subunit interfaces that comprise the site for agonist and competitive antagonist binding in more detail, the findings show that negatively charged residues cluster in domains arranged to diminish electrostatic free energy of the complex. Electrostatic factors also appear to distinguish the ligand binding interfaces, alpha gamma and alpha delta, from the other three interfaces on the pentameric receptor.

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