Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy.
Barbara J. Ebersole, Irache Visiers, Harel Weinstein, Stuart C. Sealfon
Molecular Pharmacology 2003 DOI: 10.1124/mol.63.1.36 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental and computational study Peer reviewed |
|---|---|
| Population | Human serotonin 5-HT2A receptor |
| Topics | Serotonin |
| Keywords | Drug-receptor interaction Molecular pharmacology Ligand binding Drug binding Receptor binding Drug-target interaction Serotonin 5-ht2a receptor Serotonin receptor Gpcr Neurotransmitter receptor Receptor activation Efficacy Partial agonism Signal transduction Molecular activation Molecular mechanism Drug orientation Amino acid interactions Binding mode Structural basis Drug position |
| Citations | 72 |
| Key findings | Hydrogen-bond interactions between indole agonists and Ser3.36 and Ser5.46 in the 5-HT2A receptor influence agonist position in the binding pocket and determine efficacy. |
Abstract
Based on experiment and computational simulation, we present a structural explanation for the differing efficacies of indole agonists at the human serotonin 5-HT2A receptor (5HT2AR). We find that serotonin [5-hydroxytryptamine (5-HT)] forms hydrogen-bonds with Ser3.36 in helix 3 and Ser5.46 in helix 5. Disruption of these hydrogen bonds by methyl-substitution of the cationic primary amine or of the backbone N1-amine, respectively, leads to a reduction in agonist efficacy. Computational simulation predicts that mutation of Ser3.36 to Ala should allow a similar interaction with helix 3 both for agonists that have unmodified cationic amine side chains and for those with substituted amines. Experimentally, this mutation was found to largely eliminate the differences in efficacy caused by cationic amine substitution for a series of indole congeners. Similarly, substitution of the N1-amine, which interacts with Ser5.46, reduced efficacy more markedly at the wild-type (WT) than at the Ser5.46Ala mutant receptor. Computational modeling of binding pocket interactions of ligands with WT and mutant receptor constructs demonstrate how the Ser3.36 and Ser5.46 interactions serve to modify the agonist's favored position in the binding pocket. A striking correlation was found between differences in the position assumed by the indole ring and differences in agonist activity. These data support the hypothesis that the position of the agonist interacting with the receptor is influenced by specific interactions in helices 3 and 5 and determines the degree of receptor activation by agonist through a mechanism that is likely to be shared by other G-protein coupled receptors in this class.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 17
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex Journal of Neuroscience October 1, 2003
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- Psychedelic-inspired drug discovery using an engineered biosensor. Cell April 28, 2021
- Of Roots and Fruits: A Comparison of Psychedelic and Nonpsychedelic Mystical Experiences Journal of Humanistic Psychology October 24, 2016
and 12 more in the library
Cites 2
- Mapping the binding site pocket of the serotonin 5-Hydroxytryptamine2A receptor. Ser3.36(159) provides a second interaction site for the protonated amine of serotonin but not of lysergic acid diethylamide or bufotenin. Journal of Biological Chemistry June 21, 1996
- Contribution of a helix 5 locus to selectivity of hallucinogenic and nonhallucinogenic ligands for the human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors: direct and indirect effects on ligand affinity mediated by the same locus. Molecular Pharmacology July 1, 1996