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Proc Natl Acad Sci U S A
2009 Jul 21;10629:11919-24. doi: 10.1073/pnas.0903260106.
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Probing the role of the cation-pi interaction in the binding sites of GPCRs using unnatural amino acids.
Torrice MM
,
Bower KS
,
Lester HA
,
Dougherty DA
.
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We describe a general application of the nonsense suppression methodology for unnatural amino acid incorporation to probe drug-receptor interactions in functional G protein-coupled receptors (GPCRs), evaluating the binding sites of both the M2 muscarinic acetylcholine receptor and the D2 dopamine receptor. Receptors were expressed in Xenopus oocytes, and activation of a G protein-coupled, inward-rectifying K(+) channel (GIRK) provided, after optimization of conditions, a quantitative readout of receptor function. A number of aromatic amino acids thought to be near the agonist-binding site were evaluated. Incorporation of a series of fluorinated tryptophan derivatives at W6.48 of the D2 receptor establishes a cation-pi interaction between the agonist dopamine and W6.48, suggesting a reorientation of W6.48 on agonist binding, consistent with proposed "rotamer switch" models. Interestingly, no comparable cation-pi interaction was found at the aligning residue in the M2 receptor.
Ballesteros,
Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors.
2001, Pubmed
Ballesteros,
Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors.
2001,
Pubmed
Beene,
Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine.
2002,
Pubmed
,
Xenbase
Cherezov,
High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.
2007,
Pubmed
Cho,
Hydrophobic residues of the D2 dopamine receptor are important for binding and signal transduction.
1995,
Pubmed
Dougherty,
Physical organic chemistry on the brain.
2008,
Pubmed
Dougherty,
Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp.
1996,
Pubmed
Dougherty,
Cys-loop neuroreceptors: structure to the rescue?
2008,
Pubmed
Doupnik,
RGS proteins reconstitute the rapid gating kinetics of gbetagamma-activated inwardly rectifying K+ channels.
1997,
Pubmed
,
Xenbase
Gallivan,
Cation-pi interactions in structural biology.
1999,
Pubmed
Hibert,
Three-dimensional models of neurotransmitter G-binding protein-coupled receptors.
1991,
Pubmed
Hopkins,
The druggable genome.
2002,
Pubmed
Huang,
Unnatural amino acid replacement in a yeast G protein-coupled receptor in its native environment.
2008,
Pubmed
Huang,
Construction of a sequence motif characteristic of aminergic G protein-coupled receptors.
2003,
Pubmed
Ivanina,
Mapping the Gbetagamma-binding sites in GIRK1 and GIRK2 subunits of the G protein-activated K+ channel.
2003,
Pubmed
,
Xenbase
Jaakola,
The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist.
2008,
Pubmed
Klabunde,
Drug design strategies for targeting G-protein-coupled receptors.
2002,
Pubmed
Kofuji,
Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by G beta gamma subunits and function as heteromultimers.
1995,
Pubmed
,
Xenbase
Krapivinsky,
G beta gamma binds directly to the G protein-gated K+ channel, IKACh.
1995,
Pubmed
Lagerström,
Structural diversity of G protein-coupled receptors and significance for drug discovery.
2008,
Pubmed
Lin,
Specific tryptophan UV-absorbance changes are probes of the transition of rhodopsin to its active state.
1996,
Pubmed
Lu,
Seven-transmembrane receptors: crystals clarify.
2002,
Pubmed
Lu,
The functional topography of transmembrane domain 3 of the M1 muscarinic acetylcholine receptor, revealed by scanning mutagenesis.
1999,
Pubmed
Ma,
The Cationminus signpi Interaction.
1997,
Pubmed
Mark,
G-protein mediated gating of inward-rectifier K+ channels.
2000,
Pubmed
,
Xenbase
Nowak,
In vivo incorporation of unnatural amino acids into ion channels in Xenopus oocyte expression system.
1998,
Pubmed
,
Xenbase
Palczewski,
Crystal structure of rhodopsin: A G protein-coupled receptor.
2000,
Pubmed
Rasmussen,
Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.
2007,
Pubmed
Rishal,
Gbetagamma-dependent and Gbetagamma-independent basal activity of G protein-activated K+ channels.
2005,
Pubmed
,
Xenbase
Rodriguez,
In vivo incorporation of multiple unnatural amino acids through nonsense and frameshift suppression.
2006,
Pubmed
,
Xenbase
Rodriguez,
Improved amber and opal suppressor tRNAs for incorporation of unnatural amino acids in vivo. Part 1: minimizing misacylation.
2007,
Pubmed
,
Xenbase
Rosenbaum,
GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function.
2007,
Pubmed
Sadja,
Gating of GIRK channels: details of an intricate, membrane-delimited signaling complex.
2003,
Pubmed
Schwartz,
Is there a 'lock' for all agonist 'keys' in 7TM receptors?
1996,
Pubmed
Schwartz,
Molecular mechanism of 7TM receptor activation--a global toggle switch model.
2006,
Pubmed
Shi,
Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch.
2002,
Pubmed
Shi,
The binding site of aminergic G protein-coupled receptors: the transmembrane segments and second extracellular loop.
2002,
Pubmed
Turcatti,
Probing the structure and function of the tachykinin neurokinin-2 receptor through biosynthetic incorporation of fluorescent amino acids at specific sites.
1996,
Pubmed
,
Xenbase
Warne,
Structure of a beta1-adrenergic G-protein-coupled receptor.
2008,
Pubmed
Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase
Ye,
Site-specific incorporation of keto amino acids into functional G protein-coupled receptors using unnatural amino acid mutagenesis.
2008,
Pubmed
Zacharias,
Cation-pi interactions in ligand recognition and catalysis.
2002,
Pubmed
Zhang,
Gating properties of GIRK channels activated by Galpha(o)- and Galpha(i)-coupled muscarinic m2 receptors in Xenopus oocytes: the role of receptor precoupling in RGS modulation.
2002,
Pubmed
,
Xenbase
Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed
