A cation-π interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists

TY - JOUR

T1 - A cation-π interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists

AU - Pless, Stephan Alexander

AU - Hanek, Ariele P

AU - Price, Kerry L

AU - Lynch, Joseph W

AU - Lester, Henry A

AU - Dougherty, Dennis A

AU - Lummis, Sarah C R

PY - 2011/4

Y1 - 2011/4

N2 - Cation-π interactions have been demonstrated to play a major role in agonist-binding in Cys-loop receptors. However, neither the aromatic amino acid contributing to this interaction nor its location is conserved among Cys-loop receptors. Likewise, it is not clear how many different agonists of a given receptor form a cation-π interaction or, if they do, whether it is with the same aromatic amino acid as the major physiological agonist. We demonstrated previously that Phe159 in the glycine receptor (GlyR) α1 subunit forms a strong cation-π interaction with the principal agonist, glycine. In the current study, we investigated whether the lower efficacy agonists of the human GlyR β-alanine and taurine also form cation-π interactions with Phe159. By incorporating a series of unnatural amino acids, we found cation-β interactions between Phe159 and the amino groups of β-alanine and taurine. The strengths of these interactions were significantly weaker than for glycine. Modeling studies suggest that β-alanine and taurine are orientated subtly differently in the binding pocket, with their amino groups further from Phe159 than that of glycine. These data therefore show that similar agonists can have similar but not identical orientations and interactions in the binding pocket and provide a possible explanation for the lower potencies of β-alanine and taurine.

AB - Cation-π interactions have been demonstrated to play a major role in agonist-binding in Cys-loop receptors. However, neither the aromatic amino acid contributing to this interaction nor its location is conserved among Cys-loop receptors. Likewise, it is not clear how many different agonists of a given receptor form a cation-π interaction or, if they do, whether it is with the same aromatic amino acid as the major physiological agonist. We demonstrated previously that Phe159 in the glycine receptor (GlyR) α1 subunit forms a strong cation-π interaction with the principal agonist, glycine. In the current study, we investigated whether the lower efficacy agonists of the human GlyR β-alanine and taurine also form cation-π interactions with Phe159. By incorporating a series of unnatural amino acids, we found cation-β interactions between Phe159 and the amino groups of β-alanine and taurine. The strengths of these interactions were significantly weaker than for glycine. Modeling studies suggest that β-alanine and taurine are orientated subtly differently in the binding pocket, with their amino groups further from Phe159 than that of glycine. These data therefore show that similar agonists can have similar but not identical orientations and interactions in the binding pocket and provide a possible explanation for the lower potencies of β-alanine and taurine.

KW - Amino Acid Sequence

KW - Animals

KW - Binding Sites

KW - Cations

KW - Conserved Sequence

KW - Dose-Response Relationship, Drug

KW - Female

KW - Humans

KW - Phenylalanine

KW - Receptors, Glycine

KW - Taurine

KW - Xenopus laevis

KW - beta-Alanine

U2 - 10.1124/mol.110.069583

DO - 10.1124/mol.110.069583

M3 - Journal article

C2 - 21266487

SN - 0026-895X

VL - 79

SP - 742

EP - 748

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 4

ER -