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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_2A Receptor

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana

We assessed the relative importance of two serine residues located near the top of transmembrane helix 5 of the human 5-HT_2A 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-HT_2A 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-HT_2A 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.

Address correspondence to: Dr. David E. Nichols, Dept. of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, 575 Stadium Mall Drive, Purdue University, West Lafayette, IN 47907-2091. E-mail: drdave{at}pharmacy.purdue.edu