TY - JOUR T1 - Assessment of the Roles of Serines 5.43(239) and 5.46(242) for Binding and Potency of Agonist Ligands at the Human Serotonin 5-HT<sub>2A</sub> Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1200 LP - 1209 DO - 10.1124/mol.107.039255 VL - 72 IS - 5 AU - Michael R. Braden AU - David E. Nichols Y1 - 2007/11/01 UR - http://molpharm.aspetjournals.org/content/72/5/1200.abstract N2 - We assessed the relative importance of two serine residues located near the top of transmembrane helix 5 of the human 5-HT2A receptor, comparing the wild type with S5.43(239)A or S5.46(242)A mutations. Using the ergoline lysergic acid diethylamide (LSD), and a series of substituted tryptamine and phenethylamine 5-HT2A receptor agonists, we found that Ser5.43(239) is more critical for agonist binding and function than Ser5.46(242). Ser5.43(239) seems to engage oxygen substituents at either the 4- or 5-position of tryptamine ligands and the 5-position of phenylalkylamine ligands. Even when a direct binding interaction cannot occur, our data suggest that Ser5.43(239) is still important for receptor activation. Polar ring-substituted tryptamine ligands also seem to engage Ser5.46(242), but tryptamines lacking such a substituent may adopt an alternate binding orientation that does not engage this residue. Our results are consistent with the role of Ser5.43(239) as a hydrogen bond donor, whereas Ser5.46(242) seems to serve as a hydrogen bond acceptor. These results are consistent with the functional topography and utility of our in silico-activated homology model of the h5-HT2A receptor. In addition, being more distal from the absolutely conserved Pro5.50, a strong interaction with Ser5.43(239) may be more effective in straightening the kink in helix 5, a feature that is possibly common to all type A GPCRs that have polar residues at position 5.43. The American Society for Pharmacology and Experimental Therapeutics ER -