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Titolo:
MOLECULAR MODELING OF THE HUMAN VASOPRESSIN V2 RECEPTOR AGONIST COMPLEX/
Autore:
CZAPLEWSKI C; KAZMIERKIEWICZ R; CIARKOWSKI J;
Indirizzi:
UNIV GDANSK,FAC CHEM,SOBIESKIEGO 18 PL-80952 GDANSK POLAND UNIV GDANSK,FAC CHEM PL-80952 GDANSK POLAND
Titolo Testata:
Journal of computer-aided molecular design
fascicolo: 3, volume: 12, anno: 1998,
pagine: 275 - 287
SICI:
0920-654X(1998)12:3<275:MMOTHV>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-COUPLED RECEPTORS; ELECTRON CRYOMICROSCOPY; PROJECTION STRUCTURE; BINDING-SITE; AGONIST; RHODOPSIN; OXYTOCIN; BACTERIORHODOPSIN; ACTIVATION; DYNAMICS;
Keywords:
AMBER 4.1; CONSTRAINED SIMULATED ANNEALING; GPCR; MOLECULAR DYNAMICS; RECEPTOR-AGONIST INTERACTION; VASOPRESSIN V2 RECEPTOR;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
43
Recensione:
Indirizzi per estratti:
Citazione:
C. Czaplewski et al., "MOLECULAR MODELING OF THE HUMAN VASOPRESSIN V2 RECEPTOR AGONIST COMPLEX/", Journal of computer-aided molecular design, 12(3), 1998, pp. 275-287

Abstract

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 cavitythan most of the hitherto modeled GPCR constructs do, typically basedon 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, potentiallycapable 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 wereequilibrated 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 havealready been found critical for the ligand affinity [Mouillac et al.,J. Biol. Chem, 270 (1995) 25771].

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Documento generato il 06/04/20 alle ore 21:50:40