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

Igor Tsigelny, Naova Sugiyama, Steven M Sine, Palmer Taylor

Research output: Contribution to journalArticle

68 Citations (Scopus)

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 labeling 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 α1-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, αγ and αδ, from the other three interfaces on the pentameric receptor.

Original languageEnglish (US)
Pages (from-to)52-66
Number of pages15
JournalBiophysical Journal
Volume73
Issue number1
StatePublished - Jul 1997

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Nicotinic Receptors
Static Electricity
Plastocyanin
Competitive Binding
Molecular Dynamics Simulation
Sequence Homology
Site-Directed Mutagenesis
Mechanics
Cations
Binding Sites
Ligands
Amino Acids
Antibodies
Proteins
pseudoazurin

ASJC Scopus subject areas

  • Biophysics

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A model of the nicotinic receptor extracellular domain based on sequence identity and residue location. / Tsigelny, Igor; Sugiyama, Naova; Sine, Steven M; Taylor, Palmer.

In: Biophysical Journal, Vol. 73, No. 1, 07.1997, p. 52-66.

Research output: Contribution to journalArticle

Tsigelny, Igor ; Sugiyama, Naova ; Sine, Steven M ; Taylor, Palmer. / A model of the nicotinic receptor extracellular domain based on sequence identity and residue location. In: Biophysical Journal. 1997 ; Vol. 73, No. 1. pp. 52-66.
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