A Cation-π Interaction at a Phenylalanine Residue in the Glycine Receptor Binding Site Is Conserved for Different Agonists

Pless, Stephan A.; Hanek, Ariele P.; Price, Kerry L.; Lynch, Joseph W.; Lester, Henry A.; Dougherty, Dennis A.; Lummis, Sarah C. R.

doi:10.1124/mol.110.069583

Cited by 47 publications

(46 citation statements)

References 46 publications

(74 reference statements)

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“…The slope for residue 206 (0.13) is slightly higher than for 254 (0.11), which could indicate that the cation-π interaction is stronger at the 254 site. Our recent study of cation-π interactions of different agonists in glycine receptors suggests that the exact orientation of the cationic moiety influences the strength of a cation-π interaction at a given site (Pless et al, 2011), consistent with a computational study which demonstrated that the exact orientation of the aromatic residue and the cation are crucial for a strong cation-π interaction (Gallivan and Dougherty, 2000). …”

Section: Discussionsupporting

confidence: 85%

Two Amino Acid Residues Contribute to a Cation-π Binding Interaction in the Binding Site of an Insect GABA Receptor

Lummis¹,

McGonigle²,

Ashby³

et al. 2011

J. Neurosci.

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Cys-loop receptor binding sites characteristically possess an ‘aromatic box’, where several aromatic amino acid residues surround the bound ligand. A cation-π interaction between one of these residues and the natural agonist is common, although the residue type and location are not conserved. Even in the closely related vertebrate GABAA and GABAC receptors, residues in distinct locations perform this role: in GABAA receptors a Tyr residue in loop A forms a cation-π interaction with GABA, while in GABAC receptors a loop B residue performs this role. GABA-activated Cys-loop receptors also exist in invertebrates, where they have distinct pharmacologies and are the target of a range of pesticides. Here we examine the location of GABA in an insect binding site by incorporating a series of fluorinated Phe derivatives into the receptor binding pocket using unnatural amino acid mutagenesis, and evaluating the resulting receptors when expressed in Xenopus oocytes. A homology model suggests that two aromatic residues (in loops B and C) are positioned such that they could contribute to a cation-π interaction with the primary ammonium of GABA, and the data reveal a clear correlation between the GABA EC50 and the cation-π binding ability both at Phe206 (loop B) and Tyr254 (loop C), demonstrating for the first time the contribution of two aromatic residues to a cation-π interaction in a Cys loop receptor.

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Section: Discussionsupporting

confidence: 85%

Two Amino Acid Residues Contribute to a Cation-π Binding Interaction in the Binding Site of an Insect GABA Receptor

Lummis¹,

McGonigle²,

Ashby³

et al. 2011

J. Neurosci.

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“…1C). These residues are in agreement with the data obtained from functional and mutagenesis studies regarding agonist binding (Rajendra et al, 1995;Laube et al, 2002;Pless et al, 2011;Yu et al, 2014).…”

Section: General Structure Of Cys-loop Receptorssupporting

confidence: 81%

Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

2016

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Glycine receptors (GlyR) are inhibitory Cys-loop ion channels that contribute to the control of excitability along the central nervous system (CNS). GlyR are found in the spinal cord and brain stem, and more recently they were reported in higher regions of the CNS such as the hippocampus and nucleus accumbens. GlyR are involved in motor coordination, respiratory rhythms, pain transmission, and sensory processing, and they are targets for relevant physiologic and pharmacologic modulators. Several studies with protein crystallography and cryoelectron microscopy have shed light on the residues and mechanisms associated with the activation, blockade, and regulation of pentameric Cys-loop ion channels at the atomic level. Initial studies conducted on the extracellular domain of acetylcholine receptors, ion channels from prokaryote homologs-Erwinia chrysanthemi ligand-gated ion channel (ELIC), Gloeobacter violaceus ligand-gated ion channel (GLIC)-and crystallized eukaryotic receptors made it possible to define the overall structure and topology of the Cys-loop receptors. For example, the determination of pentameric GlyR structures bound to glycine and strychnine have contributed to visualizing the structural changes implicated in the transition between the open and closed states of the Cys-loop receptors. In this review, we summarize how the new information obtained in functional, mutagenesis, and structural studies have contributed to a better understanding of the function and regulation of GlyR.

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“…Moreover, this approach is helpful, because it allows for the straightforward comparison of the present study with other previously characterized cation-pi systems through the relative slope of the plot. For instance, viewing our results in light of previously confirmed cation-pi interactions in ligand-gated channels where, although the drug/receptor ratio is different (1:1 for anti-arrhythmic drugs and sodium channels; at least 2:1 for pentameric ligand-gated channels and their agonists), the slopes of the cation-pi plots for lidocaine and mexiletine ( − 0.08 and − 0.06, respectively) are similar to those observed for activation of the nicotinic acetylcholine receptor with acetylcholine ( − 0.11) 35 and the activation of the glycine receptor with β-alanine and taurine ( − 0.12 and − 0.09, respectively) 36 .…”

Section: Resultsmentioning

confidence: 52%

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

et al. 2011

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Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.

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A Cation-π Interaction at a Phenylalanine Residue in the Glycine Receptor Binding Site Is Conserved for Different Agonists

Cited by 47 publications

References 46 publications

Two Amino Acid Residues Contribute to a Cation-π Binding Interaction in the Binding Site of an Insect GABA Receptor

Two Amino Acid Residues Contribute to a Cation-π Binding Interaction in the Binding Site of an Insect GABA Receptor

Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

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