MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ebersole, B. J.
Right arrow Articles by Sealfon, S. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ebersole, B. J.
Right arrow Articles by Sealfon, S. C.

Vol. 63, Issue 1, 36-43, January 2003

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, and Stuart C. Sealfon

Departments of Neurology (B.J.E., S.C.S.), Physiology and Biophysics (I.V., H.W.), Pharmacology and Biological Chemistry (H.W., S.C.S.), and the Fishberg Research Center in Neurobiology (S.C.S.), Mount Sinai School of Medicine, New York, New York

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.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
J. D. Urban, W. P. Clarke, M. von Zastrow, D. E. Nichols, B. Kobilka, H. Weinstein, J. A. Javitch, B. L. Roth, A. Christopoulos, P. M. Sexton, et al.
Functional Selectivity and Classical Concepts of Quantitative Pharmacology
J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 1 - 13.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
M. Foucaud, I. G. Tikhonova, I. Langer, C. Escrieut, M. Dufresne, C. Seva, B. Maigret, and D. Fourmy
Partial Agonism, Neutral Antagonism, and Inverse Agonism at the Human Wild-Type and Constitutively Active Cholecystokinin-2 Receptors
Mol. Pharmacol., March 1, 2006; 69(3): 680 - 690.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Herrick-Davis, E. Grinde, T. J. Harrigan, and J. E. Mazurkiewicz
Inhibition of Serotonin 5-Hydroxytryptamine2C Receptor Function through Heterodimerization: RECEPTOR DIMERS BIND TWO MOLECULES OF LIGAND AND ONE G-PROTEIN
J. Biol. Chem., December 2, 2005; 280(48): 40144 - 40151.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. N. McLaughlin, L. Shen, M. Holinstat, J. D. Brooks, E. DiBenedetto, and H. E. Hamm
Functional Selectivity of G Protein Signaling by Agonist Peptides and Thrombin for the Protease-activated Receptor-1
J. Biol. Chem., July 1, 2005; 280(26): 25048 - 25059.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Kortagere, P. Gmeiner, H. Weinstein, and J. A. Schetz
Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain
Mol. Pharmacol., December 1, 2004; 66(6): 1491 - 1499.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
J. Gonzalez-Maeso, T. Yuen, B. J. Ebersole, E. Wurmbach, A. Lira, M. Zhou, N. Weisstaub, R. Hen, J. A. Gingrich, and S. C. Sealfon
Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex
J. Neurosci., October 1, 2003; 23(26): 8836 - 8843.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2003 by the American Society for Pharmacology and Experimental Therapeutics