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-HT2A receptor.
Michael R Braden, David E Nichols
Molecular Pharmacology November 2007 DOI: 10.1124/mol.107.039255 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key points | Ser5.43(239) of the human 5-HT2A receptor is reported to be more critical for agonist binding and function than Ser5.46(242), engaging oxygen substituents on tryptamine and phenylalkylamine ligands; the authors propose Ser5.43(239) acts as a hydrogen bond donor and Ser5.46(242) as a hydrogen bond acceptor, and that Ser5.43(239) may promote helix 5 straightening. |
Abstract
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.
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Citations in the library
Cited by 24
- Structural Basis for Molecular Recognition at Serotonin Receptors Science March 22, 2013
- Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties PLoS Computational Biology April 19, 2012
- Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens. Current Topics in Behavioral Neurosciences 2017
- N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues. ACS Chemical Neuroscience July 15, 2015
- Structure–activity relationships of serotonin 5‐HT2Aagonists Wiley Interdisciplinary Reviews Membrane Transport and Signalling February 28, 2012
and 19 more in the library
Cites 5
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- Differential phospholipase C activation by phenylalkylamine serotonin 5‐HT2Areceptor agonists Journal of Neurochemistry November 8, 2005
- C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2AReceptor Journal of Medicinal Chemistry June 21, 2006
- Hallucinogens. Pharmacology & Therapeutics February 1, 2004
- Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats. Psychopharmacology October 2002