Molecular modeling of the human vasopressin V2 receptor/agonist complex

被引:36
作者
Czaplewski, C [1 ]
Kazmierkiewicz, R [1 ]
Ciarkowski, J [1 ]
机构
[1] Univ Gdansk, Fac Chem, PL-80952 Gdansk, Poland
关键词
AMBER; 4.1; constrained simulated annealing; GPCR; molecular dynamics; receptor-agonist interaction; vasopressin V2 receptor;
D O I
10.1023/A:1007969526447
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The V2 vasopressin renal receptor (V2R), which controls antidiuresis in mammals, is a member of the large family of heptahelical transmembrane (7TM) G protein-coupled receptors (GPCRs). Using the automated GPCR modeling facility available via Internet (http://expasy.hcuge.ch/swissmod/SWISS-MODEL.html) for construction of the 7TM domain in accord with the bovine rhodopsin (RD) footprint, and the SYBYL software for addition of the intra- and extracellular domains, the human V2R was modeled. The structure was further refined and its conformational variability tested by the use of a version of the Constrained Simulated Annealing (CSA) protocol developed in this laboratory An inspection of the resulting structure reveals that the V2R (likewise any GPCR modeled this way) is much thicker and accordingly forms a more spacious TM cavity than most of the hitherto modeled GPCR constructs do, typically based on the structure of bacteriorhodopsin (BRD). Moreover, in this model the 7TM helices are arranged differently than they are in any BRD-based model. Thus, the topology and geometry of the TM cavity, potentially capable of receiving Ligands, is in this model quite different than it is in the earlier models. In the subsequent step, two ligands, the native [arginines] vasopressin (AVP) and the selective agonist [D-arginine(8)]vasopressin (DAVP) were inserted, each in two topologically non-equivalent ways, into the TM cavity and the resulting structures were equilibrated and their conformational variabilities tested using CSA as above. The best docking was selected and justified upon consideration of ligand-receptor interactions and structure-activity data. Finally, the amino acid residues were indicated, mainly in TM helices 3-7, as potentially important in both AVP and DAVP docking. Among those Cys(112), Val(115)-Lys(116), Gln(119), Met(123) in helix 3; Glu(174) in helix 4; Val(206), Ala(210), Val(213)-Phe(214) in helix 5; Trp(284), Phe(287)-Phe(288), Gln(291) in helix 6; and Phe(307), Leu(310), Ala(314) and Asn(317) in helix 7 appeared to be the most important ones. Many of these residues are invariant for either the GPCR superfamily or the neurophyseal (vasopressin V2R, V1aR and V1bR and oxytocin OR) subfamily of receptors. Moreover, some of the equivalent residues in V1aR have already been found critical for the ligand affinity [Mouillac et al., J. Biol. Chem, 270 (1995) 25771].
引用
收藏
页码:275 / 287
页数:13
相关论文
共 43 条
[21]   A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Novel mixed mode Monte Carlo stochastic dynamics simulations of the complex between TRH and TRH receptor [J].
Laakkonen, LJ ;
Guarnieri, F ;
Perlman, JH ;
Gershengorn, MC ;
Osman, R .
BIOCHEMISTRY, 1996, 35 (24) :7651-7663
[22]  
LASZLO FA, 1991, PHARMACOL REV, V43, P73
[23]   Different single receptor domains determine the distinct G protein coupling profiles of members of the vasopressin receptor family [J].
Liu, J ;
Wess, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (15) :8772-8778
[24]   THE BINDING-SITE OF NEUROPEPTIDE VASOPRESSIN V1A RECEPTOR - EVIDENCE FOR A MAJOR LOCALIZATION WITHIN TRANSMEMBRANE REGIONS [J].
MOUILLAC, B ;
CHINI, B ;
BALESTRE, MN ;
ELANDS, J ;
TRUMPPKALLMEYER, S ;
HOFLACK, J ;
HIBERT, M ;
JARD, S ;
BARBERIS, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (43) :25771-25777
[25]  
PEARLMAN DA, 1995, AMBER 4 1
[26]  
PEARLMAN JH, 1996, BIOCHEMISTRY-US, V35, P7643
[27]   Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V-2 vasopressin receptor [J].
Postina, R ;
Kojro, E ;
Fahrenholz, F .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (49) :31593-31601
[28]  
SAYLE R, 1996, RASMOL V 2 6
[29]   Constitutively active mutants of the alpha(1B)-adrenergic receptor: Role of highly conserved polar amino acids in receptor activation [J].
Scheer, A ;
Fanelli, F ;
Costa, T ;
DeBenedetti, PG ;
Cotecchia, S .
EMBO JOURNAL, 1996, 15 (14) :3566-3578
[30]   Constitutively active G protein-coupled receptors: Potential mechanisms of receptor activation [J].
Scheer, A ;
Cotecchia, S .
JOURNAL OF RECEPTOR AND SIGNAL TRANSDUCTION RESEARCH, 1997, 17 (1-3) :57-73