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Titolo:
MUTAGENESIS REVEALS STRUCTURE-ACTIVITY PARALLELS BETWEEN HUMAN A(2A)-ADENOSINE RECEPTORS AND BIOGENIC-AMINE G-PROTEIN-COUPLED RECEPTORS
Autore:
JIANG QL; LEE BX; GLASHOFER M; VANRHEE AM; JACOBSON KA;
Indirizzi:
NIDDK,MOL RECOGNIT SECT,LBC,NIH,BLDG 8A,RM B1A-17 BETHESDA MD 20892 NIDDK,MOL RECOGNIT SECT,LBC,NIH BETHESDA MD 20892
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 16, volume: 40, anno: 1997,
pagine: 2588 - 2595
SICI:
0022-2623(1997)40:16<2588:MRSPBH>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
SITE-DIRECTED MUTAGENESIS; LIGAND-BINDING-SITE; BETA-ADRENERGIC-RECEPTOR; TRANSMEMBRANE DOMAIN; 3-DIMENSIONAL MODELS; ANTAGONIST BINDING; IDENTIFICATION; RESIDUES; AGONIST; ACTIVATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
50
Recensione:
Indirizzi per estratti:
Citazione:
Q.L. Jiang et al., "MUTAGENESIS REVEALS STRUCTURE-ACTIVITY PARALLELS BETWEEN HUMAN A(2A)-ADENOSINE RECEPTORS AND BIOGENIC-AMINE G-PROTEIN-COUPLED RECEPTORS", Journal of medicinal chemistry, 40(16), 1997, pp. 2588-2595

Abstract

Structure-affinity relationships for ligand binding at the human A(2A) adenosine receptor have been probed using site-directed mutagenesis in the transmembrane helical domains (TMs). The mutant receptors were expressed in COS-7 cells and characterized by binding of the radioligands [H-3]CGS21680; [H-3]NECA, and [H-3]XAC. Three residues, at positions essential for ligand binding in other G protein-coupled receptors, were individually mutated. The residue V(3.32) in the A(2A) receptor that is homologous to the essential aspartate residue of TM3 in the biogenic amine receptors, i.e., V84(3.32), may be substituted with L (present in the A(3) receptor) but not with D (in biogenic amine receptors) or A. H250(6.52), homologous to the critical N507 of rat m3 muscarinic acetylcholine receptors, may be substituted with other aromatic residues or with N but not with A (Kim et al. J. Biol. Chem. 1995, 270, 13987-13997). H278(7.43) homologous to the covalent ligand anchor site in rhodopsin, may not be substituted with either A, K, or N. Both V84L(3.32) and H250N(6.52) mutant receptors were highly variable in their effect on ligand competition depending on the structural class of the ligand. Adenosine-5'-uronamide derivatives were more potent at the H250N(6.52) mutant receptor than at wild type receptors. Xanthines tendedto be close in potency (H250N(6.52)) or less potent (V84L(3.32)) thanat wild type receptors. The affinity of CGS21680 increased as the pH was lowered to 5.5 in both the wild type and H250N(6.52) mutant receptors. Thus, protonation of H250(6.52) is not involved in this pH dependence. These data are consistent with a molecular model predicting the proximity of bound agonist ligands to TM3, TM5, TM6, and TM7.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 07:06:04