JPET

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
Right arrow Citation Map
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 Thibonnier, M.
Right arrow Articles by Shoham, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Thibonnier, M.
Right arrow Articles by Shoham, M.

Vol. 294, Issue 1, 195-203, July 2000

A Molecular Model of Agonist and Nonpeptide Antagonist Binding to the Human V1 Vascular Vasopressin Receptor1

Marc Thibonnier, Patrick Coles, Doreen M. Conarty, Christine L. Plesnicher and Menachem Shoham

Departments of Medicine (M.T., D.M.C., C.L.M.) and Biochemistry (P.C., M.S.), Case Western Reserve University School of Medicine, Cleveland, Ohio

The affinity of the nonpeptide antagonist OPC-21268 is greater for the rat V1 arginine vasopressin (AVP) receptor (V1R) than for the human V1R. Site-specific mutagenesis was carried out to identify the residues that determine interspecies selectivity for nonpeptide antagonist binding. The introduction of rat amino acids in position 224, 310, 324, or 337 of the human V1R sequence dramatically altered OPC-21268 affinity for the receptor, whereas binding of AVP, the peptide V1R antagonist d(CH2)5Tyr(Me)AVP, and the nonpeptide V1R antagonist SR49059 was not altered by these mutations. Computer modeling explained the mutagenesis results. Docking of OPC-21268 onto a homology-built model of the V1R receptor yielded a model for the bound ligand in which the hydrophobic part is deeply embedded in the transmembrane region, whereas the polar part is located on the surface of the extracellular side. The increased affinity of the G337A mutant is due to two additional van der Waals contacts of the alanine methyl group with carbon atoms on the antagonist. The I310V mutant reduces the hydrophobicity in the vicinity of the polar oxygen atom of the antagonist. The I224V mutant relieves overcrowding in a hydrophobic binding pocket involving the aromatic residues Trp175, Phe179, Phe307, and Trp304. Finally, the E324D mutant enables the formation of a hydrogen bond of the carboxylate side chain with the amide side chain of Gln311, which in turn forms a hydrogen bond with the N57 nitrogen atom of OPC-21268. Thus, a few residues, distinct from those involved in agonist binding, control interspecies selectivity toward OPC-21268 nonpeptide antagonist binding.

1 This work was supported in part by National Institutes of Health Grants RO1-HL39757 and PO1-HL41618. P.C. was supported by an Undergraduate Research Experience supplement to Grant MCB97-28420 from the National Science Foundation awarded to M.S.

0022-3565/00/2941-0195$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Mol. Endocrinol.Home page
J. Rodrigo, A. Pena, B. Murat, M. Trueba, T. Durroux, G. Guillon, and D. Rognan
Mapping the Binding Site of Arginine Vasopressin to V1a and V1b Vasopressin Receptors
Mol. Endocrinol., February 1, 2007; 21(2): 512 - 523.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. Macion-Dazard, N. Callahan, Z. Xu, N. Wu, M. Thibonnier, and M. Shoham
Mapping the Binding Site of Six Nonpeptide Antagonists to the Human V2-Renal Vasopressin Receptor
J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 564 - 571.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
A Levoye, B Mouillac, G Riviere, D Vieau, M Salzet, and C Breton
Cloning, expression and pharmacological characterization of a vasopressin-related receptor in an annelid, the leech Theromyzon tessulatum
J. Endocrinol., January 1, 2005; 184(1): 277 - 289.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Acharjee, J.-L. Do-Rego, D. Y. Oh, R. S. Ahn, H. Choe, H. Vaudry, K. Kim, J. Y. Seong, and H. B. Kwon
Identification of Amino Acid Residues That Direct Differential Ligand Selectivity of Mammalian and Nonmammalian V1a Type Receptors for Arginine Vasopressin and Vasotocin: INSIGHTS INTO MOLECULAR COEVOLUTION OF V1a TYPE RECEPTORS AND THEIR LIGANDS
J. Biol. Chem., December 24, 2004; 279(52): 54445 - 54453.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
S. Derick, A. Pena, T. Durroux, J. Wagnon, C. Serradeil-Le Gal, M. Hibert, D. Rognan, and G. Guillon
Key Amino Acids Located within the Transmembrane Domains 5 and 7 Account for the Pharmacological Specificity of the Human V1b Vasopressin Receptor
Mol. Endocrinol., November 1, 2004; 18(11): 2777 - 2789.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. J. Reinhart, Q. Xie, X.-J. Liu, Y.-F. Zhu, J. Fan, C. Chen, and R. S. Struthers
Species Selectivity of Nonpeptide Antagonists of the Gonadotropinreleasing Hormone Receptor Is Determined by Residues in Extracellular Loops II and III and the Amino Terminus
J. Biol. Chem., August 13, 2004; 279(33): 34115 - 34122.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Tahtaoui, M.-N. Balestre, P. Klotz, D. Rognan, C. Barberis, B. Mouillac, and M. Hibert
Identification of the Binding Sites of the SR49059 Nonpeptide Antagonist into the V1a Vasopressin Receptor Using Sulfydryl-reactive Ligands and Cysteine Mutants as Chemical Sensors
J. Biol. Chem., October 10, 2003; 278(41): 40010 - 40019.
[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 © 2000 by the American Society for Pharmacology and Experimental Therapeutics.