A molecular model of agonist and nonpeptide antagonist binding to the human V1 vascular vasopressin receptor
Abstract
The affinity of the nonpeptide antagonist OPC-21268 is greater for the rat V(1) arginine vasopressin (AVP) receptor (V(1)R) than for the human V(1)R. 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 V(1)R sequence dramatically altered OPC-21268 affinity for the receptor, whereas binding of AVP, the peptide V(1)R antagonist d(CH(2))(5)Tyr(Me)AVP, and the nonpeptide V(1)R 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 V(1)R 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 Trp(175), Phe(179), Phe(307), and Trp(304). Finally, the E324D mutant enables the formation of a hydrogen bond of the carboxylate side chain with the amide side chain of Gln(311), 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.
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AVP binding involves interactions with amino acid residues in all three extracellular loop elements and residues in the N-terminus proximal to the first TM segment.
“AVP binding, in contrast, involves interactions with amino acid residues in all three extracellular loop elements and residues in the N-terminus proximal to the first TM segment. (Hawtin et al., 2005; Thibonnier et al., 2000).”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Thibonnier et al., 2000
Saimiri, Callithrix, and Callicebus all have a S213P substitution, predicted to interact with the AVP ligand.
“Saimiri, Callithrix, and Callicebus all have a S213P substitution, which is predicted using computer simulations to interact with the AVP ligand (Thibonnier et al., 2000).”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Thibonnier et al., 2000
Many changes in the V1aR N-terminus are not in the AVP binding region, which is proximal to the first TM segment.
“It is worth noting that many of the changes in the V1aR N-terminus are not in the AVP binding region, which is proximal to the first TM segment (Hawtin et al., 2005; Thibonnier et al., 2000).”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Thibonnier et al., 2000
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- Authors
- Thibonnier, M., Coles, P., Conarty, D. M., Plesnicher, C. L., & Shoham, M.
- Affiliations
- Case Western Reserve University (US)
- ORCID
- Thibonnier, Marc
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 294
- Issue
- 1
- Pages
- 195-203
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2267647105
- Cited by
- 35
- References
- 36
- Citations by year
- 2026: 1 · 2023: 2 · 2016: 2 · 2015: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Heart, Lung, and Blood Institute (R01HL039757, P01HL041618)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- V1 vasopressin receptor, vasopressin, OPC-21268, site-directed mutagenesis, molecular docking, homology model, ligand-receptor interactions, van der Waals contacts, hydrogen bonding, hydrophobic pocket, d(CH2)5Tyr(Me)AVP
- MeSH terms
- Amino Acid Sequence, Animals, Arginine Vasopressin, Humans, Models, Molecular, Molecular Sequence Data, Piperidines, Radioligand Assay, Quinolones, Mutagenesis, Site-Directed, Receptors, Vasopressin, Rats, Antidiuretic Hormone Receptor Antagonists
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