Docking of Linear Peptide Antagonists into the Human V1a Vasopressin Receptor

Phalipou, Sylvie; Seyer, René; Cotte, Nathalie; Breton, Christophe; Barberis, Claude; Hibert, Marcel; Mouillac, Bernard

doi:10.1074/jbc.274.33.23316

Cited by 38 publications

(77 citation statements)

References 42 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This model has been extensively tested by means of site-directed mutagenesis (Mouillac et al 1995) and successfully used to identify the receptor residues responsible for selective agonist binding affinity (Chini et al 1995) and efficacy (Chini et al 1996). It has also been recently exploited to explain the pharmacological behaviour of the vasopressin 2 (V,) receptor mutants responsible for clinical forms of congenital nephrogenic diabetes insipidus (Ala et al Albertazzi et al 2000), and to identify the putative docking site for peptidergic linear antagonists in the VIa receptor subtype (Phalipou et al 1999). …”

Section: Oxytocin and Vasopressin Receptor Binding Sitesmentioning

confidence: 99%

Molecular basis of ligand binding and receptor activation in the oxytocin and vasopressin receptor family

Chini

Fanelli

2000

Experimental Physiology

View full text Add to dashboard Cite

Although it is now widely accepted that G-protein-coupled receptors exist in at least two allosteric states, inactive and active, and that the spontaneous equilibrium between the two is regulated by various events including the binding of specific agonists and antagonists, the molecular counterparts of these functionally different states are still poorly understood. In this paper, we review our current knowledge concerning the structure-function relationships of the oxytocin and vasopressin receptors, focusing in particular on the process of receptor activation. Using a combined approach of site-directed mutagenesis and molecular modelling, we investigated the molecular events leading to agonist-dependent and -independent receptor activation in the human oxytocin receptor. Our analysis allows us to propose that the active Conformations of this receptor are characterised by similar rearrangements of its cytosolic regions that ultimately lead to the opening of a putative docking site for the G-protein. Furthermore, the dynamics of these motions are similar to that observed in the a,,-adrenergic receptor, thus suggesting that, although activated by different ligands, the process of receptor isomerization in these two receptors is regulated by the same cluster of highly conserved residues and that common molecular events are responsible for receptor activation in different G-protein-coupled receptors. Experimental Physiology (2000) 85S, 59S-66S.Oxytocin and vasopressin receptors belong to the superfamily of G-protein-coupled receptors. These are integral membrane proteins characterised by the presence of seven hydrophobic transmembrane domains that are predicted to fold in an a-helical conformation and to be connected by extracellular and intracellular hydrophilic loops.

show abstract

Section: Oxytocin and Vasopressin Receptor Binding Sitesmentioning

confidence: 99%

Molecular basis of ligand binding and receptor activation in the oxytocin and vasopressin receptor family

Chini

Fanelli

2000

Experimental Physiology

View full text Add to dashboard Cite

show abstract

“…1) in the human V 1a receptor, we used 3D models of the rat and human AVP receptors [4,16,17,21]. These models suggest that hydrophobic residues potentially involved in the ligand binding are aromatic and localized at the bottom of the receptor binding pocket.…”

Section: R E S U L T Smentioning

confidence: 99%

“…Studies of chimeric OT/V 2 receptors have shown that TM VII contributes to the binding of an OT antagonist [15]. To identify the receptor domains that contribute to the binding of V 1a antagonists, we developed two radioiodinated photosensitive ligands used to covalently label the human V 1a receptor [16,17]. Combining photoaffinity labeling and receptor fragmentation, we clearly demonstrated that covalent attachment of the antagonists occurs in TM VII and in the first extracellular loop of the receptor, respectively.…”

mentioning

confidence: 99%

“…A rapid interconversion between different b-turn geometries and multiple slowly exchanging conformations were observed for AVP and for the antagonists, respectively. Taking into account these structural data and our previous findings describing that the binding sites for peptide agonists/linear peptide antagonists partially overlap in the receptor TM core [4,16,17], we hypothesized that AVP and its cyclic peptide antagonist d(CH 2 ) 5 [Tyr(Me)2]AVP could occupy the same transmembrane binding pocket in the V 1a receptor.…”

mentioning

confidence: 99%

“…In the present study, based on the 3D models of the rat and human AVP receptors [4,16,17,21], and in order to determine residues of the human V 1a receptor able to differentiate binding of AVP and d(CH 2 ) 5 [Tyr(Me)2]AVP antagonist, conserved aromatic or hydrophilic, as well as nonconserved residues, were mutated. The consequences on the ligand affinity were determined.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Conserved aromatic residues in the transmembrane region VI of the V1a vasopressin receptor differentiate agonist vs. antagonist ligand binding

et al. 2000

Self Cite

View full text Add to dashboard Cite

Despite their opposite effects on signal transduction, the nonapeptide hormone arginine-vasopressin (AVP) and its V 1a receptor-selective cyclic peptide antagonist d(CH 2 ) 5 [Tyr(Me)2]AVP display homologous primary structures, differing only at residues 1 and 2. These structural similarities led us to hypothesize that both ligands could interact with the same binding pocket in the V 1a receptor. To determine receptor residues responsible for discriminating binding of agonist and antagonist ligands, we performed site-directed mutagenesis of conserved aromatic and hydrophilic residues as well as nonconserved residues, all located in the transmembrane binding pocket of the V 1a receptor. Mutation of aromatic residues of transmembrane region VI (W304, F307, F308) reduced affinity for the d(CH 2 ) 5 [Tyr(Me)2]AVP and markedly decreased affinity for the unrelated strongly hydrophobic V 1a -selective nonpeptide antagonist SR 49059. Replacement of these aromatic residues had no effect on AVP binding, but increased AVP-induced coupling efficacy of the receptor for its G protein. Mutating hydrophilic residues Q108, K128 and Q185 in transmembrane regions II, III and IV, respectively, led to a decrease in affinity for both agonists and antagonists. Finally, the nonconserved residues T333 and A334 in transmembrane region VII, controlled the V 1a /V 2 binding selectivity for both nonpeptide and cyclic peptide antagonists. Thus, because conserved aromatic residues of the V 1a receptor binding pocket seem essential for antagonists and do not contribute at all to the binding of agonists, we propose that these residues differentiate agonist vs. antagonist ligand binding.Keywords: vasopressin receptors; antagonist-binding sites; signal transduction; site-directed mutagenesis; three-dimensional model. G protein-coupled receptors (GPCR) constitute an extremely important target in medicinal chemistry. Thus, there is considerable interest in the docking of the natural ligands and their analogues to these receptors, both for rational drug design and for a better understanding of their functional architecture. To date, the structures of binding sites of peptide hormones have been elucidated primarily by a combination of molecular modeling hypotheses and validation by site-directed mutagenesis analysis (reviewed in [1±3]). Such an approach was applied to the receptors specific for the mammalian hormones arginine-vasopressin (AVP) and oxytocin (OT), which constitute typical GPCR. Indeed, a detailed 3D model of bound AVP to the rat V 1a receptor has been developed and then experimentally verified [4]. Interestingly, AVP binds to its receptor in a hydrophobic pocket of 15±20 A Ê defined by the transmembrane regions (TMs), in a position similar to that of the cationic neurotransmitters [5]. The residues responsible for the binding of AVP are highly conserved and the agonist-binding site was proposed to be common through the different AVP/OT receptor subtypes. Molecular modeling of the V 2 receptor, docking of the hormone and peptide structu...

show abstract

Organoselenium Compounds in Medicinal Chemistry

Gallo‐Rodriguez,

Rodriguez

2024

ChemMedChem

View full text Add to dashboard Cite

The chemical and biological interest in this element and the molecules bearing selenium has been exponentially growing over the years. Selenium, formerly designated as a toxin, becomes a vital trace element for life that appears as selenocysteine and its dimeric form, selenocystine, in the active sites of selenoproteins, which catalyze a wide variety of reactions, including the detoxification of reactive oxygen species and modulation of redox activities. From the point of view of drug developments, organoselenium drugs are isosteres of sulfur‐containing and oxygen—containing drugs with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. This statement is the paramount relevance considering the big number of clinically employed compounds bearing sulfur or oxygen atoms if their structures including nucleosides and carbohydrates. Thus, in this article we have focused on the relevant features of the application of selenium in medicinal chemistry. With the increasing interest in selenium chemistry, we have attempted to highlight the most significant published data on this subject, mainly concentrating the analysis on the last years. In consequence, the recent advances of relevant pharmacological organoselenium compounds are discussed.

show abstract

Docking of Linear Peptide Antagonists into the Human V1a Vasopressin Receptor

Cited by 38 publications

References 42 publications

Molecular basis of ligand binding and receptor activation in the oxytocin and vasopressin receptor family

Molecular basis of ligand binding and receptor activation in the oxytocin and vasopressin receptor family

Conserved aromatic residues in the transmembrane region VI of the V1a vasopressin receptor differentiate agonist vs. antagonist ligand binding

Organoselenium Compounds in Medicinal Chemistry

Contact Info

Product

Resources

About