HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Almaula, N. Articles by Sealfon, S. C. Search for Related Content PubMed PubMed Citation Articles by Almaula, N. Articles by Sealfon, S. C. Social Bookmarking                      What's this?

Volume 271, Number 25, Issue of June 21, 1996 pp. 14672-14675
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

---

COMMUNICATION:
Mapping the Binding Site Pocket of the Serotonin 5-Hydroxytryptamine_2A Receptor
Ser^3.36(159) PROVIDES A SECOND INTERACTION SITE FOR THE PROTONATED AMINE OF SEROTONIN BUT NOT OF LYSERGIC ACID DIETHYLAMIDE OR BUFOTENIN

(Received for publication, April 17, 1996)

Niva Almaula , Barbara J. Ebersole ^§¶ , Daqun Zhang , Harel Weinstein ^¶ and Stuart C. Sealfon ^''

From the  Fishberg Research Center in Neurobiology, Departments of ^§ Anesthesiology,  Physiology and Biophysics, ^¶ Pharmacology, and ^'' Neurology, Mount Sinai School of Medicine, New York, New York 10029

Like other amine neurotransmitters that activate G-protein-coupled receptors, 5-hydroxytryptamine (5-HT) binds to the 5-HT_2A receptor through the interaction of its cationic primary amino group with the conserved Asp^3.32(155) in transmembrane helix 3. Computational experiments with a 5-HT_2A receptor model suggest that the same functional group of 5-hydroxytryptamine also forms a hydrogen bond with the side chain of Ser^3.36(159), which is adjacent in space to Asp^3.32(155). However, other 5-HT_2A receptor ligands like lysergic acid diethylamide (LSD), in which the amine nitrogen is embedded in a heterocycle, or N,N-dimethyl 5-HT, in which the side chain is a tertiary amine, are found in the computational simulations to interact with the aspartate but not with the serine, due mainly to steric hindrance. The predicted difference in the interaction of various ligands in the same receptor binding pocket was tested with site-directed mutagenesis of Ser^3.36(159)  Ala and Ser^3.36(159)  Cys. The alanine substitution led to an 18-fold reduction in 5-HT affinity and the cysteine substitution to an intermediate 5-fold decrease. LSD affinity, in contrast, was unaffected by either mutation. N,N-Dimethyl 5-HT affinity was unaffected by the cysteine mutation and had a comparatively small 3-fold decrease in affinity for the alanine mutant. These findings identify a mode of ligand-receptor complexation that involves two receptor side chains interacting with the same functional group of specific serotonergic ligands. This interaction serves to orient the ligands in the binding pocket and may influence the degree of receptor activation.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. P. Harris, V. M. Hapiak, R. T. Wragg, S. B. Miller, L. J. Hughes, R. J. Hobson, R. Steven, B. Bamber, and R. W. Komuniecki Three Distinct Amine Receptors Operating at Different Levels within the Locomotory Circuit Are Each Essential for the Serotonergic Modulation of Chemosensation in Caenorhabditis elegans J. Neurosci., February 4, 2009; 29(5): 1446 - 1456. [Abstract] [Full Text] [PDF]

				V. M. Hapiak, R. J. Hobson, L. Hughes, K. Smith, G. Harris, C. Condon, P. Komuniecki, and R. W. Komuniecki Dual Excitatory and Inhibitory Serotonergic Inputs Modulate Egg Laying in Caenorhabditis elegans Genetics, January 1, 2009; 181(1): 153 - 163. [Abstract] [Full Text] [PDF]

				R. T. Wragg, V. Hapiak, S. B. Miller, G. P. Harris, J. Gray, P. R. Komuniecki, and R. W. Komuniecki Tyramine and Octopamine Independently Inhibit Serotonin-Stimulated Aversive Behaviors in Caenorhabditis elegans through Two Novel Amine Receptors J. Neurosci., December 5, 2007; 27(49): 13402 - 13412. [Abstract] [Full Text] [PDF]

				M. C. Clark, T. E. Dever, J. J. Dever, P. Xu, V. Rehder, M. A. Sosa, and D. J. Baro Arthropod 5-HT2 Receptors: A Neurohormonal Receptor in Decapod Crustaceans That Displays Agonist Independent Activity Resulting from an Evolutionary Alteration to the DRY Motif J. Neurosci., March 31, 2004; 24(13): 3421 - 3435. [Abstract] [Full Text] [PDF]

				B. J. Ebersole, I. Visiers, H. Weinstein, and S. C. Sealfon Molecular Basis of Partial Agonism: Orientation of Indoleamine Ligands in the Binding Pocket of the Human Serotonin 5-HT2A Receptor Determines Relative Efficacy Mol. Pharmacol., January 1, 2003; 63(1): 36 - 43. [Abstract] [Full Text] [PDF]

				P. Manivet, B. Schneider, J. C. Smith, D.-S. Choi, L. Maroteaux, O. Kellermann, and J.-M. Launay The Serotonin Binding Site of Human and Murine 5-HT2B Receptors. MOLECULAR MODELING AND SITE-DIRECTED MUTAGENESIS J. Biol. Chem., May 3, 2002; 277(19): 17170 - 17178. [Abstract] [Full Text] [PDF]

				D. A. Shapiro, K. Kristiansen, D. M. Weiner, W. K. Kroeze, and B. L. Roth Evidence for a Model of Agonist-induced Activation of 5-Hydroxytryptamine 2A Serotonin Receptors That Involves the Disruption of a Strong Ionic Interaction between Helices 3 and 6 J. Biol. Chem., March 22, 2002; 277(13): 11441 - 11449. [Abstract] [Full Text] [PDF]

				J. A. Ballesteros, L. Shi, and J. A. Javitch Structural Mimicry in G Protein-Coupled Receptors: Implications of the High-Resolution Structure of Rhodopsin for Structure-Function Analysis of Rhodopsin-Like Receptors Mol. Pharmacol., July 1, 2001; 60(1): 1 - 19. [Abstract] [Full Text]

				I. Visiers, S. A. Hassan, and H. Weinstein Differences in conformational properties of the second intracellular loop (IL2) in 5HT2C receptors modified by RNA editing can account for G protein coupling efficiency Protein Eng. Des. Sel., June 1, 2001; 14(6): 409 - 414. [Abstract] [Full Text] [PDF]

				M. C. Gershengorn and R. Osman Minireview: Insights into G Protein-Coupled Receptor Function Using Molecular Models Endocrinology, January 1, 2001; 142(1): 2 - 10. [Abstract] [Full Text] [PDF]

				D. A. Shapiro, K. Kristiansen, W. K. Kroeze, and B. L. Roth Differential Modes of Agonist Binding to 5-Hydroxytryptamine2A Serotonin Receptors Revealed by Mutation and Molecular Modeling of Conserved Residues in Transmembrane Region 5 Mol. Pharmacol., November 1, 2000; 58(5): 877 - 886. [Abstract] [Full Text]

				K. Kristiansen, W. K. Kroeze, D. L. Willins, E. I. Gelber, J. E. Savage, R. A. Glennon, and B. L. Roth A Highly Conserved Aspartic Acid (Asp-155) Anchors the Terminal Amine Moiety of Tryptamines and Is Involved in Membrane Targeting of the 5-HT2A Serotonin Receptor But Does Not Participate in Activation via a "Salt-Bridge Disruption" Mechanism J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 735 - 746. [Abstract] [Full Text]

				S. Barroso, F. Richard, D. Nicolas-Etheve, J.-L. Reversat, J.-M. Bernassau, P. Kitabgi, and C. Labbe-Jullie Identification of Residues Involved in Neurotensin Binding and Modeling of the Agonist Binding Site in Neurotensin Receptor 1 J. Biol. Chem., January 7, 2000; 275(1): 328 - 336. [Abstract] [Full Text] [PDF]

				J. Sanders, Y. Oda, S. Roberts, A. Kiddie, T. Richards, J. Bolton, V. McGrath, S. Walters, D. Jaskolski, J. Furmaniak, et al. The Interaction of TSH Receptor Autoantibodies with 125I-Labelled TSH Receptor J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3797 - 3802. [Abstract] [Full Text] [PDF]

				B. L. Roth, D. L. Willins, K. Kristiansen, and W. K. Kroeze Activation is Hallucinogenic and Antagonism is Therapeutic: Role of 5-HT2A Receptors in Atypical Antipsychotic Drug Actions Neuroscientist, July 1, 1999; 5(4): 254 - 262. [Abstract] [PDF]

				J. Ballesteros, S. Kitanovic, F. Guarnieri, P. Davies, B. J. Fromme, K. Konvicka, L. Chi, R. P. Millar, J. S. Davidson, H. Weinstein, et al. Functional Microdomains in G-protein-coupled Receptors. THE CONSERVED ARGININE-CAGE MOTIF IN THE GONADOTROPIN-RELEASING HORMONE RECEPTOR J. Biol. Chem., April 24, 1998; 273(17): 10445 - 10453. [Abstract] [Full Text] [PDF]

				M. Han, M. Groesbeek, T. P. Sakmar, and S. O. Smith The C9 methyl group of retinal interacts with glycine-121 in rhodopsin PNAS, December 9, 1997; 94(25): 13442 - 13447. [Abstract] [Full Text] [PDF]

				B. L. Roth, M. Shoham, M. S. Choudhary, and N. Khan Identification of Conserved Aromatic Residues Essential for Agonist Binding and Second Messenger Production at 5-Hydroxytryptamine2A Receptors Mol. Pharmacol., August 1, 1997; 52(2): 259 - 266. [Abstract] [Full Text]

				S. C. Sealfon, H. Weinstein, and R. P. Millar Molecular Mechanisms of Ligand Interaction with the Gonadotropin-Releasing Hormone Receptor Endocr. Rev., April 1, 1997; 18(2): 180 - 205. [Abstract] [Full Text]

				M. Han, S. W. Lin, S. O. Smith, and T. P. Sakmar The Effects of Amino Acid Replacements of Glycine 121on Transmembrane Helix 3of Rhodopsin J. Biol. Chem., December 13, 1996; 271(50): 32330 - 32336. [Abstract] [Full Text] [PDF]

				M. Han, S. W. Lin, M. Minkova, S. O. Smith, and T. P. Sakmar Functional Interaction of Transmembrane Helices 3and 6in Rhodopsin. REPLACEMENT OF PHENYLALANINE 261BY ALANINE CAUSES REVERSION OF PHENOTYPE OF A GLYCINE 121REPLACEMENT MUTANT J. Biol. Chem., December 13, 1996; 271(50): 32337 - 32342. [Abstract] [Full Text] [PDF]

				Y.-M. Sun, C. A. Flanagan, N. Illing, T. R. Ott, R. Sellar, B. J. Fromme, J. Hapgood, P. Sharp, S. C. Sealfon, and R. P. Millar A Chicken Gonadotropin-releasing Hormone Receptor That Confers Agonist Activity to Mammalian Antagonists. IDENTIFICATION OF D-LYS6 IN THE LIGAND AND EXTRACELLULAR LOOP TWO OF THE RECEPTOR AS DETERMINANTS J. Biol. Chem., March 9, 2001; 276(11): 7754 - 7761. [Abstract] [Full Text] [PDF]

				H. Frang, V. Cockcroft, T. Karskela, M. Scheinin, and A. Marjamaki Phenoxybenzamine Binding Reveals the Helical Orientation of the Third Transmembrane Domain of Adrenergic Receptors J. Biol. Chem., August 10, 2001; 276(33): 31279 - 31284. [Abstract] [Full Text] [PDF]