Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 18, 2005; DOI: 10.1124/jpet.105.095554
0022-3565/06/3162-564-571$20.00
JPET 316:564-571, 2006
CELLULAR AND MOLECULAR
Mapping the Binding Site of Six Nonpeptide Antagonists to the Human V2-Renal Vasopressin Receptor
Rosemarie Macion-Dazard,
Nicholas Callahan,
Zhen Xu1,
Nan Wu,
Marc Thibonnier, and
Menachem Shoham
Departments of Biochemistry (R.M.-D., N.C., Z.X., N.W., M.S.) and Medicine (M.T.), Case Western Reserve University, Cleveland, Ohio
Received for publication
September 12, 2005
Accepted
October 14, 2005.
 |
Abstract
|
|---|
Whereas arginine vasopressin binds to its receptor subtypes V1R and V2R with equal affinity of approximately 2 nM, nonpeptide antagonists interact differently with vasopressin receptor subtypes. The V2R antagonist binding site was mapped by site-directed mutagenesis at six selected amino acid positions, K100D, A110W, M120V, L175Y, R202S, and F307I, predicted to be involved in antagonist binding differences between V2 R and V1R. These mutations did not alter the affinity for arginine vasopressin. However, the affinity for six nonpeptide receptor antagonists SR121463B [1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]-5-ethoxy-3-spiro-[4[(2 morpholinoethoxy)cy-clohexane]indoline-2-one, phosphate monohydrate cis-isomer], SR49059 [(2S)1-[(2R3S)-(5-chloro-3-(2 chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide], SSR149415 [(2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2pyrrolidine carboxamide, isomer(-)], OPC21268 [1-[1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl]-3,4-dihydro-2(1H)-quinolinone], OPC41061 [(±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-o-tolu-m-toluidide], and OPC31260, [(±)-5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-1,2, 3,4,5-tetrahydro-1H-benzazepine monohydrochloride], was altered to varying degrees, resulting in differences up to 6000-fold. Replacement of the small alanine for the bulky tryptophan in position 110 resulted in a reduced affinity for all six antagonists. In contrast, replacement of the large methionine for the smaller valine in position 120 caused a dramatic increase in affinity, up to a Ki of 7 fM for OPC31260. Molecular modeling revealed that the binding sites for arginine vasopressin and the nonpeptide antagonists are partially overlapping. Whereas arginine vasopressin binds on the extracellular surface of V2 R, the nonpeptide antagonists penetrate deeper into the transmembrane region of the receptor, in particular OPC21268. The mutagenesis data point to significant differences in the shape of the V1R and V2R antagonist binding pockets. The most important factor determining the specificity of nonpeptide antagonists seems to be the shape of the binding pocket on the receptor.
Arginine vasopressin (AVP), the antidiuretic hormone, is a cyclic nonapeptide that modulates various physiological functions, such as water reabsorption, blood volume, blood pressure, cellular proliferation, and adrenocorticotropic hormone secretion (Thibonnier et al., 1998
, 2001). The antidiuretic effect of AVP is mediated by the vasopressin V2 receptor (V2R), a member of the large family of G protein-coupled receptors (Robben et al., 2004). V2R is a 41-kDa seven-transmembrane protein of 371 residues (Birnbaumer et al., 1992). V2R is expressed in the basolateral membrane of epithelial cells of the renal distal tubule and the collecting ducts (Hermosilla et al., 2004; Robben et al., 2004). In the collecting duct of the kidney, AVP binds to the V2R, thereby activating the Gs/adenylyl cyclase system. The subsequent rise in intracellular cAMP levels induces protein kinase A to phosphorylate, among other proteins, the human water-channel aquaporin-2, which relocates from the intracellular vesicles to the apical membrane, resulting in free water reabsorption and urine concentration (Robben et al., 2004).
View larger version (56K):
[in this window]
[in a new window]
|
Fig. 1. Snake diagram of human V2R. Residues in white represent amino acids that are identical in human V1R and V2R, whereas shaded residues are the divergent amino acids. The two tandem cysteine residues in the C-terminal segment are palmytoylated, thus providing a membrane anchor. Arrows show selected mutations K100D, A110W, M120V, L175Y, R202S, and F307I. The box represents the putative ligand-binding pocket.
|
|
Specific mutations in V2R cause loss of function or dysregulation of V2R in patients with X-linked congenital nephrogenic diabetes insipidus (NDI) (Morello and Bichet, 2001; Robben et al., 2004). Patients suffering from NDI are unable to concentrate urine despite elevated circulating levels of AVP (Wenkert et al., 1996). To date, more than 150 distinct NDI-causing mutations within the V2R gene structure have been described. In some instances, the functional consequences of the mutation are easily understood because of the presence of premature stop codons or frameshifts, leading to severely truncated or altered nonfunctional receptor proteins. Up to 70% of these mutations result in transport-defective receptors that fail to reach the cellular membrane surface (Morello et al., 2000b; Hermosilla et al., 2004).
The AVP/oxytocin receptor family represents a suitable system to investigate structure-function relationships of receptor subtypes. Pharmacological and molecular cloning studies of the V1, V2, and V3 AVP receptors, as well as the related oxytocin receptor, have shown that these peptide receptors display a great diversity in their functional properties despite high sequence homology. These receptors can bind not only the native hormone AVP but also potent and selective cyclic and linear peptide analogs, as well as nonpeptide antagonists (Cotte et al., 1998). Mutagenesis studies have indicated that the ligand-binding pocket includes residues located on the extracellular loops as well as in adjoining transmembrane helices of the receptors (Oksche et al., 2002).
In this work, we set out to determine key residues responsible for the differential nonpeptide ligand binding specificity to V2R versus V1R. Six nonconservative single amino acid differences between the V2R and the V1R sequences (K100D, A110W, M120V, L175Y, R202S, and F307I) were selected for this investigation because of their location within the putative ligand binding pocket. The amino acid in position 202 is particularly interesting, because an R202C mutation has been identified in patients suffering from NDI (Morello and Bichet, 2001). Dissociation constants of the six nonpeptide receptor antagonists for each mutant V2R were determined. The data were interpreted by molecular modeling of antagonist docking to wild-type and mutant receptors. The results point to differences between the V1R and V2R antagonist binding sites. The most important factor in determining the specificity of nonpeptide antagonists seems to be the shape of the binding pocket on the receptor.
View larger version (15K):
[in this window]
[in a new window]
|
Fig. 2. Saturation binding curve of [3H]AVP to wild-type V2R. The concentration of free AVP was calculated from the difference between total and bound AVP, as described under Materials and Methods.
|
|
View larger version (73K):
[in this window]
[in a new window]
|
Fig. 3. A, chemical structure of AVP. B, surface representation of AVP docked onto the model of V2R. The view is from the outside of the cell looking down at the receptor. The extracellular loops have been omitted for clarity. The receptor surface is set to 50% transparency. AVP and residues selected for mutagenesis are in ball-and-stick representation. Nitrogen is blue, oxygen is red, and sulfur is orange, and carbon is magenta on the ligand, yellow on the mutated side chains, and green on the rest of the receptor. The amino acid one-letter code of AVP and V2R residues is in lowercase and uppercase, respectively. This figure was generated with program PyMOL.
|
|
|
Materials and Methods
|
|---|
Chemicals
Tritiated [Arg8]vasopressin (60 Ci/mmol) was obtained from American Radiolabeled Chemicals (St. Louis, MO). [Arg8]Vasopressin was obtained from Bachem (Bubendorf, Switzerland). OPC31260, OPC21268, and OPC41061 were kindly provided by Otsuka Pharmaceutical, Inc. (Tokyo, Japan). SR121463B, SR49059, and SSR149415 were kindly provided by sanofi-synthelabo (Toulouse, France).
Construction of Receptor Expression Plasmids
Wild-Type V2R-GFP. The human V2R cDNA (comprising the coding region, nucleotides 219-1354 of the human cDNA sequence, GenBank accession number 4895106) was isolated from pcDNA plasmid by XbaI/BamHI digest and subcloned into the XbaI/BamHI-cut pEGFP-N1 plasmid (BD Biosciences Clontech, Palo Alto, CA) for comparative expression analysis.
Mutant V2R-GFP. Plasmids encoding mutants K100D, A110W, M120V, L175Y, R202S, and F307I were generated with the QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA) following manufacturer's instructions. The wild-type V2R-GFP plasmid was used as template. Sense and antisense primers encoding single amino acid changes were purchased from Invitrogen (Carlsbad, CA). The sequence of each construct was checked by Cleveland Genomics, Inc. (Cleveland, OH).
Cell Culture and Transfection
Chinese hamster ovary-K1 cells (American Type Culture Collection, Manassas, VA) were grown in F-12K medium (Invitrogen) supplemented with 10% fetal calf serum (Invitrogen) and 500 units/ml penicillin/streptomycin (Invitrogen) in an atmosphere of 95% air and 5% CO2 at 37°C. Stable transfection was done using the Lipofectamine 2000 transfection kit (Invitrogen) following the manufacturer's instructions. The stable cell lines of wild type and mutants were selected by flow-cytometry sorting (Cancer Center Core Facility, Case Western Reserve University) and G418 (Invitrogen) selection up to 8 or 12 µg/ml.
Radioligand Binding Assays
The binding of [3H]AVP to intact Chinese hamster ovary cells was performed as described previously (Thibonnier et al., 2000). In brief, the cells were seeded at a density of 1.75 x 105/well in 12-well plates. Twenty-four hours after plating, the cells were washed twice with binding buffer (10 mM MgCl2, 0.2% bovine serum albumin in 1x Dulbecco's phosphate-buffered saline, pH 7.4). For saturation binding analysis, the cells were then incubated with increasing concentrations of [3H]AVP diluted in the same buffer in the presence (nonspecific binding) or absence (total binding) of 100 nM unlabeled AVP for 30 min at 30°C in a shaking water bath. For competition binding analysis, cells were incubated with 2 nM [3H]AVP in the presence of increasing concentrations of unlabeled AVP or nonpeptide antagonist for 30 min at 30°C in a shaking water bath. After washing three times with ice-cold phosphate-buffered saline, the cells were lysed with 0.1 N NaOH and 0.1% SDS. The lysates were then transferred to scintillation vials, and 4 ml of ReadyProtein (Beckman Coulter, Inc., Fullerton, CA) scintillation cocktail was added. Radioactivity was determined in a liquid scintillation counter (LS6000; Beckman Coulter). Kd and inhibition constant (Ki) values were calculated using standard equations and program Prism 4.0 (GraphPad Software, Inc., San Diego, CA) (Thibonnier et al., 2000).
Molecular Modeling
A molecular model of V2R was built based upon a model of V1R, previously established in this laboratory (Thibonnier et al., 2000). Program O was used to visualize the amino acid replacement models (Jones et al., 1991). Energy minimization was carried out with program CNS (Brunger et al., 1998).
Docking of AVP and Antagonists to the V2R Model
Docking of AVP and antagonists was carried out with the program LIGIN (Sobolev et al., 1996). The docking was done for each compound and for each chimeric receptor separately followed by energy minimization with program CNS. Ligand-receptor distances were calculated with the program CONTACT within the CCP4 suite of crystallographic programs (Collaborative Computational Project, Number 4, 1994).
|
Results
|
|---|
Selection of Point Mutants. Previous studies have localized the binding site for AVP and its antagonists in a region delineated by the extracellular loops and the adjoining transmembrane regions of the V2R (Thibonnier et al., 2002). To further map the binding site and to identify residues responsible for the specificity of antagonists binding to V1 and V2 receptor subtypes, point mutations were created by introducing into the V2R sequence the corresponding residues from the V1R sequence. The degree of sequence identity between V2R and V1R is 65, 44, and 21% for the extracellular loops el1, el2, and el3, respectively. The overall degree of sequence identity is 41%, high enough to assume that the overall fold of these two receptors is conserved. Because there are many sequence differences, we wanted to select mutations that potentially affect antagonist specificity. Twenty point mutations were initially selected within the putative ligand-binding region based on the nonconservative nature of the amino acid replacements. The number of point mutants employed in this study was eventually reduced to the following six-well expressed mutants: K100D, A110W, M120V, L175Y, R202S, and F307I. The criteria for selecting these mutations include charge reversal (K100D), large changes in the volume of the side chain (A110W, M120V, and R202S), and replacements of aliphatic to aromatic side chains or vice versa (L175Y and F307I). The location of these mutations in V2R is shown in Fig. 1. Mutations K100D, A110W, R202S, and F307I are depicted on extracellular loops, whereas mutations M120V and L175Y are shown in transmembrane helices. However, there is some degree of uncertainty in assigning the boundaries between transmembrane regions and loops. For example, residue Phe-307 has been reported to be on transmembrane helix 7 (Mouillac et al., 1995).
Affinity of AVP for the V2R Mutants. The affinity of AVP for the wild-type V2R, as determined by saturation binding experiments with [3H]AVP, is 2.2 nM (Fig. 2), identical to the value we reported previously (see Table 1) (Thibonnier et al., 2001). None of the six point mutations affected AVP affinity for the V2R in any significant way. In silico docking of AVP to V2R explains these findings for each of the receptor mutant. Four of the six mutated V2R residues make contact with AVP, namely Lys-100, Met-120, Leu-175, and Phe-307 (Fig. 3). Mutations at these positions do not affect the affinity, apparently for the following reasons. Residue 100 makes only backbone contacts with AVP; therefore, replacement of the side chain should has no effect on binding AVP. Mutations in the remaining three positions do not seem to alter interactions with AVP. Methionine and valine at position 120 both exhibit hydrophobic contacts with f3 and q4 of AVP. Leucine and tyrosine at position 175 both make hydrophobic contacts with backbone atoms of q4 and n5 of AVP. Phenylalanine and isoleucine at position 307 both make hydrophobic contacts with the AVP-disulfide bridge between c1 and c6 of AVP. The docking results provide an explanation for the lack of any significant effect of these amino acid replacements from V2R to the corresponding residues in V1R on the affinity for AVP. The concept of nonpeptide antagonists acting as molecular chaperones to restore agonist binding (Morello et al., 2000a) does not apply to these mutants as they all bind AVP with the same affinity as wild-type V2R. However, these mutations greatly affect binding of nonpeptide antagonists.
Affinity of the Six Nonpeptide Antagonists for the V2R Mutants. Figure 4 shows the chemical structure of the six nonpeptide antagonists used in this study. There is only partial overlap between the receptor binding sites of the antagonists and AVP. As shown in Fig. 5, at variance with AVP, the antagonists penetrate deeper into the transmembrane region of the receptor, in particular OPC21268. Docking onto V2R reveals that all six mutated residues are involved in binding nonpeptide antagonists. However, not all of the six residues are in contact with any given specific antagonist (Table 2).
View this table:
[in this window]
[in a new window]
|
TABLE 2 Docking results of nonpeptide antagonist to a molecular model of V2R Contacts to residues subjected to mutagenesis.
|
|
View larger version (27K):
[in this window]
[in a new window]
|
Fig. 6. Competition binding curves of [3H]AVP in the presence of antagonists. A, binding of [3H]AVP to wild-type V2R as a function of antagonist concentration. SR31260 and OPC21268 do not displace AVP from the receptor. B, binding of [3H]AVP to the A110W mutant as a function antagonist concentration. SSR14915 and OPC21268 do not displace [3H]AVP to any significant degree. C, binding of [3H]AVP to wild-type and mutant V2R as a function of OPC31260 concentration. This antagonist is able to completely displace [3H]AVP in the case of the A110W mutant. For the M120V and F307I mutants, the displacement is partial. OPC31260 does not displace [3H]AVP at all in the case of wild-type and mutants K100D, L175Y, and R202S.
|
|
Modeling of the Antagonists Binding to the V2R. The results of the [3H]AVP/antagonist competition binding experiments with the six selected nonpeptide antagonists and the six V2R/V1R mutants are shown in Fig. 6, and the Ki values are summarized in Table 3.
View this table:
[in this window]
[in a new window]
|
TABLE 3 Affinity (Ki, nM) of AVP and six nonpeptide antagonists for the wild type and mutated V2Rs determined by competition binding experiments with [3H]AVP
|
|
Antagonist Binding to the K100D Mutant. Large differences in the affinity of this mutant are confined to SR49059 (14-fold weaker affinity) and OPC41061 (6-fold stronger affinity). Interestingly, docking followed by energy refinement did not show any direct involvement of residue 100 in the binding of these two compounds. It is possible that the K100D mutation causes a conformational change, which indirectly affects the binding of SR49059 and OPC41061.
Antagonist Binding to the A110W Mutant. A110W is the only mutation that dramatically weakens the binding of all six nonpeptide antagonists, particularly for SSR14915 and OPC21268. For these two antagonists, no binding at all could be detected. A likely explanation for the decrease in affinity is overcrowding due to the introduction of the bulky tryptophan in place of the small alanine side chain. To relieve steric strain, the nearby Leu-175 has to adopt a different conformation, which probably results in a loss of hydrophobic interactions of this residue with antagonists (Fig. 7). Tryptophan in position 110 may also affect the nearby Arg-202, which interacts with some of the antagonists. The decrease in affinity ranges from 42-fold for SR121463B to 1340-fold for OPC41061. The binding of all nonpeptide antagonists to this mutant is also weaker than the binding of AVP by a factor up to 
200-fold.
Antagonist Binding to the M120V Mutant. This mutant exhibits the most dramatic improvement of the affinity of all six nonpeptide antagonists, with a 500- to 6000-fold decrease in Ki values. In general, the OPC compounds are more tightly bound than the SR compounds. For instance, the affinity of OPC31260 for the M120V mutant V2R is very high, with a Ki of only 7 fM. The reason for this amazing increase in affinity is probably because of relief of overcrowding by the smaller valine compared with the more bulky methionine. This introduces more flexibility into the system, which provides for an improved fit of the ligand to the receptor. Thus, it seems that entropic contributions to the binding free energy are very important in this case. However, enthalpy changes must also be favorable, because increased flexibility allows for better interactions between aromatic moieties of the ligand and the receptor (Fig. 7). This effect is more pronounced for the OPC compounds, which generally have more aromatic moieties than the SR compounds.
Antagonist Binding to the L175Y Mutant. Although unlabeled AVP could displace [3H]AVP from this mutated receptor, all six nonpeptide antagonists prevented the binding of [3H]AVP, even at antagonist concentration as low as femtomolar. The most likely explanation is that antagonist binding is so tight that AVP cannot displace it. The increased affinity may be due to hydrogen bonds of the tyrosine hydroxyl group as well as 
-stacking of the tyrosine ring with the aromatic moieties of the compounds.
Antagonist Binding to the R202S Mutant. This mutation has distinct effects on the binding characteristics of one SR and one OPC compound. There is no change in the affinity for OPC41061, whereas there is a 10-fold increase in the affinity for SR121463B. Docking of OPC41061 suggests that this antagonist makes no interactions with residue 202, whether it is an arginine or a serine. In contrast, docking of SR121463B suggests short contacts of this antagonist with the guanido group of Arg-202. Substitution of the large arginine for the smaller serine improves binding, apparently because of relief of overcrowding.
View larger version (60K):
[in this window]
[in a new window]
|
Fig. 8. The ligand-binding site on the V2R. The view is from the extracellular side perpendicular to the membrane. Docked AVP is shown in ball-and-stick representation with dark gray bonds. Docked OPC41061 is shown as an example of a nonpeptide antagonist in ball-and-stick representation with light gray bonds. The N-terminal extracellular segment and the extracellular loops 1 and 2 have been omitted for clarity. The binding sites for AVP and the nonpeptide antagonists partially overlap. The overall size of the ligand binding pocket is 25 x 20 x 15 Å.
|
|
Antagonist Binding to the F307I Mutant. Phe-307 makes a very important contribution to the binding of the antagonists, because modeling suggests that this residue is involved in binding all six nonpeptide antagonists (Table 2). The mutation to isoleucine at this position increases the affinity for all six nonpeptide antagonists by a factor of ranging from 10-fold for SR49059 to 375-fold for OPC41061. This phenomenon might be a consequence of the environment of residue 307, which is aliphatic in character. An isoleucine at this position can make better hydrophobic interactions with neighboring Leu-302 and Met-311. The latter residue is involved in binding OPC41061, according to modeling. Thus, an isoleucine at position 307 seems to position the receptor better for binding to the antagonists.
|
Discussion
|
|---|
Our findings suggest that AVP and the nonpeptide antagonists fit tightly into the binding pocket of the V2R. Docking indicates an overall binding pocket of dimensions 25 x 20 x 15 Å, with the first dimension parallel to the surface of the membrane (Fig. 8). AVP binds to a subpocket of size 22 x 14 x 14Å. The nonpeptide antagonists occupy a subpocket of dimensions 12 x 20 x 10 Å. The investigated mutations affect only the subpocket for nonpeptide antagonists. Narrowing of this ligand-binding subpocket with the A110W mutation interferes with binding. In contrast, widening of the pocket by the M120V and the F307I mutations improves antagonist binding. These results point to a significant difference in the shape of the nonpeptide antagonist binding pocket between V1R and V2R. In V1R, the single small-to- large mutation investigated in this work, A110W, is apparently compensated by three large-to-small mutations, K100D, M120V, and R202S. None of the single point mutants by themselves is responsible for nonpeptide antagonist specificity toward a particular receptor subtype. Rather, the cumulative effect of multiple mutations seems to determine receptor subtype specificity. These findings may help design more potent and selective nonpeptide AVP receptor antagonists.
|
Acknowledgements
|
|---|
We thank Claudine Serradeil-Le Gal from sanofi-synthelabo for providing us with the nonpeptide antagonists SR121463B, SR49059, and SSR14915; Koji Komuro from Otsuko Pharmaceutical Company for providing us with the nonpeptide antagonists OPC21268, OPC41061, and OPC31260; Bryan Roth, Vincent Setola, and Jonathan Birkes for help with radioligand binding assays; and the Flow Cytometry Core Facility at Case Western Reserve University for expert assistance in cell sorting.
|
Footnotes
|
|---|
This work was supported by National Institutes of Health Grant R01 HL-39757 (to M.S. and M.T.) and by a National Kidney Foundation of Ohio Research Grant (to N.W.).
doi:10.1124/jpet.105.095554.
ABBREVIATIONS: AVP, 8-arginine vasopressin; V1R, V1-vascular vasopressin receptor; V2R, V2-renal vasopressin receptor; NDI, nephrogenic diabetes insipidus; GFP, green fluorescent protein; OPC21268, 1-[1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl]-3,4-dihydro-2(1H)-quinolinone; OPC41061, (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-o-tolu-m-toluidide; OPC31260, (±)-5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-1,2,3,4,5-tetrahydro-1H-benzazepine monohydrochloride; SR49059, (2S)1-[(2R3S)-(5-chloro-3-(2 chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide; SR121463B, 1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]-5-ethoxy-3-spiro-[4[(2 morpholinoethoxy)cy-clohexane]indoline-2-one, phosphate monohydrate cis-isomer; SSR149415, (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2pyrrolidine carboxamide, isomer(-); SR, SR49059 and SR121463B; OPC, OPC31260, OPC41061, and OPC21268.
1 Current affiliation: Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH. 
Address correspondence to: Menachem Shoham, Department of Biochemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4935. E-mail: mxs10{at}case.edu
|
References
|
|---|
Birnbaumer M, Seibold A, Gilbert S, Ishido M, Barberis C, Antaramian A, Brabet P, and Rosenthal W (1992) Molecular cloning of the receptor for human antidiuretic hormone. Nature (Lond) 357: 333-335.[CrossRef][Medline]
Brunger AT, Adams PD, Clore GM, DeLano WL, Gros P, Grosse-Kunstleve RW, Jiang JS, Kuszewski J, Nilges M, Pannu NS, et al. (1998) Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr Sec D 54: 905-921.[CrossRef][Medline]
Collaborative Computational Project, Number 4. (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr Sec D 50: 760-763.[CrossRef][Medline]
Cotte N, Balestre MN, Phalipou S, Hibert M, Manning M, Barberis C, and Mouillac B (1998) Identification of residues responsible for the selective binding of peptide antagonists and agonists in the V2 vasopressin receptor. J Biol Chem 273: 29462-29468.[Abstract/Free Full Text]
Esnouf RM (1999) Further additions to MolScript version 1.4, including reading and contouring of electron-density maps. Acta Crystallogr Sec D 55: 938-940.[CrossRef][Medline]
Hermosilla R, Oueslati M, Donalies U, Schonenberger E, Krause E, Oksche A, Rosenthal W, and Schulein R (2004) Disease-causing V(2) vasopressin receptors are retained in different compartments of the early secretory pathway. Traffic 5: 993-1005.[CrossRef][Medline]
Jones TA, Zou JY, Cowan SW, and Kjeldgaard (1991) Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr Sec A 47: 110-119.
Merritt EA and Murphy ME (1994) Raster3D version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr Sec D 50: 869-873.[CrossRef][Medline]
Morello JP and Bichet DG (2001) Nephrogenic diabetes insipidus. Annu Rev Physiol 63: 607-630.[CrossRef][Medline]
Morello JP, Petaja-Repo UE, Bichet DG, and Bouvier M (2000a) Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21: 466-469.[CrossRef][Medline]
Morello JP, Salahpour A, Laperriere A, Bernier V, Arthus MF, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, et al. (2000b) Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Investig 105: 887-895.[Medline]
Mouillac B, Chini B, Balestre MN, Elands J, Trumpp-Kallmeyer S, Hoflack J, Hibert M, Jard S, and Barberis C (1995) The binding site of neuropeptide vasopressin V1a receptor. Evidence for a major localization within transmembrane regions. J Biol Chem 270: 25771-25777.[Abstract/Free Full Text]
Oksche A, Leder G, Valet S, Platzer M, Hasse K, Geist S, Krause G, Rosenthal A, and Rosenthal W (2002) Variant amino acids in the extracellular loops of murine and human vasopressin V2 receptors account for differences in cell surface expression and ligand affinity. Mol Endocrinol 16: 799-813.[Abstract/Free Full Text]
Robben JH, Knoers NV, and Deen PM (2004) Regulation of the vasopressin V2 receptor by vasopressin in polarized renal collecting duct cells. Mol Biol Cell 15: 5693-5699.[Abstract/Free Full Text]
Sobolev V, Wade RC, Vriend G, and Edelman M (1996) Molecular docking using surface complementarity. Proteins Struct Funct Genet 25: 120-129.[CrossRef][Medline]
Thibonnier M, Coles P, Conarty DM, Plesnicher CL, and Shoham M (2000) A molecular model of agonist and nonpeptide antagonist binding to the human V(1) vascular vasopressin receptor. J Pharmacol Exp Ther 294: 195-203.[Abstract/Free Full Text]
Thibonnier M, Coles P, Thibonnier A, and Shoham M (2001) The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists. Annu Rev Pharmacol Toxicol 41: 175-202.[CrossRef][Medline]
Thibonnier M, Coles P, Thibonnier A, and Shoham M (2002) Molecular pharmacology and modeling of vasopressin receptors. Prog Brain Res 139: 179-196.[Medline]
Thibonnier M, Conarty DM, Preston JA, Wilkins PL, Berti-Mattera LN, and Mattera R (1998) Molecular pharmacology of human vasopressin receptors. Adv Exp Med Biol 449: 251-276.[Medline]
Wenkert D, Schoneberg T, Merendino JJ Jr, Rodriguez Pena MS, Vinitsky R, Goldsmith PK, Wess J, and Spiegel AM (1996) Functional characterization of five V2 vasopressin receptor gene mutations. Mol Cell Endocrinol 124: 43-50.[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
L. Rihakova, C. Quiniou, F. F. Hamdan, R. Kaul, S. Brault, X. Hou, I. Lahaie, P. Sapieha, D. Hamel, Z. Shao, et al.
VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist
Am J Physiol Regulatory Integrative Comp Physiol,
October 1, 2009;
297(4):
R1009 - R1018.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Robben, M. Sze, N. V. A. M. Knoers, and P. M. T. Deen
Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus
Am J Physiol Renal Physiol,
January 1, 2007;
292(1):
F253 - F260.
[Abstract]
[Full Text]
[PDF]
|
|
|
![[Feedback]](/icons/banner/feedbackACT.gif)
![[For Subscribers]](/icons/banner/subscriberACT.gif)
![[Archive]](/icons/banner/archiveACT.gif)
![[Search]](/icons/banner/searchACT.gif)
![[Contents]](/icons/banner/tocACT.gif)
Top
Abstract
Materials and Methods
