Probing the role of the cation-pi interaction in the binding sites of GPCRs using unnatural amino acids. Export

@article{citeulike:5233495, abstract = {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.}, author = {Torrice, Michael M. and Bower, Kiowa S. and Lester, Henry A. and Dougherty, Dennis A.}, citeulike-article-id = {5233495}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0903260106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/29/11919.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/29/11919.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19581583}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19581583}, day = {21}, doi = {10.1073/pnas.0903260106}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {acids, amino, cation, gpcr, interaction, pi, torric09pdf, unnatural}, month = {July}, number = {29}, pages = {11919--11924}, posted-at = {2009-07-23 01:14:31}, priority = {2}, title = {Probing the role of the cation-pi interaction in the binding sites of GPCRs using unnatural amino acids.}, url = {http://dx.doi.org/10.1073/pnas.0903260106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:5233495 L3 - citeulike-article-id:5233495 N2 - 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. IS - 29 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 EP - 11924 TI - Probing the role of the cation-pi interaction in the binding sites of GPCRs using unnatural amino acids. VL - 106 SP - 11919 KW - acids KW - amino KW - cation KW - gpcr KW - interaction KW - pi KW - torric09pdf KW - unnatural AU - Torrice, Michael AU - Bower, Kiowa AU - Lester, Henry AU - Dougherty, Dennis PY - 2009/07/21/ UR - http://dx.doi.org/10.1073/pnas.0903260106 ER -