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Titolo:
A NEW APPROACH TO DOCKING IN THE BETA(2)-ADRENERGIC RECEPTOR THAT EXPLOITS THE DOMAIN-STRUCTURE OF G-PROTEIN-COUPLED RECEPTORS
Autore:
GOULDSON PR; SNELL CR; REYNOLDS CA;
Indirizzi:
UNIV ESSEX,DEPT CHEM & BIOL CHEM,WIVENHOE PK COLCHESTER CO4 3SQ ESSEXENGLAND UNIV ESSEX,DEPT CHEM & BIOL CHEM COLCHESTER CO4 3SQ ESSEX ENGLAND NOVARTIS INST MED SCI LONDON WC1E 6BN ENGLAND
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 24, volume: 40, anno: 1997,
pagine: 3871 - 3886
SICI:
0022-2623(1997)40:24<3871:ANATDI>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
BETA-ADRENERGIC-RECEPTOR; DOPAMINE D2 RECEPTOR; BINDING-SITE CREVICE; MEMBRANE-SPANNING SEGMENT; TACHYKININ NK-1 RECEPTOR; LIGAND-BINDING; TRANSMEMBRANE DOMAINS; POINT MUTATION; ELECTRON CRYOMICROSCOPY; 3-DIMENSIONAL STRUCTURE;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
112
Recensione:
Indirizzi per estratti:
Citazione:
P.R. Gouldson et al., "A NEW APPROACH TO DOCKING IN THE BETA(2)-ADRENERGIC RECEPTOR THAT EXPLOITS THE DOMAIN-STRUCTURE OF G-PROTEIN-COUPLED RECEPTORS", Journal of medicinal chemistry, 40(24), 1997, pp. 3871-3886

Abstract

A novel technique for docking ligands to the beta(2)-adrenergic receptor is described which exploits the domain structure of this class of receptors. The ligands (norepinephrine, an agonist; pindolol, a partial agonist; and propranolol, an antagonist) were docked into the receptor using the key conserved aspartate on helix 3 (D-113) as an initial guide to the placement of the amino group and GRID maps (Goodford, P. J. J. Med. Chem. 1985, 28, 849) to identify the likely binding regionsof the hydrophobic (and hydroxyl) moieties on the A domain (comprising of helices 1-5). The essence of the new approach involved pulling the B domain, which includes helices 6 and 7, away from the other domainby 5-7 Angstrom. During the subsequent minimization and molecular dynamics, the receptor ligand complex reformed to yield structures which were very well supported by site-directed mutagenesis data. In particular, the model predicted a number of important interactions between the antagonist and key residues on helix 7 (notably Leu(311) and Asn(312)) which have not been described in many previous computer simulation studies. The justification for this new approach is discussed in termsof(a) phase space sampling and (b) mimicking the natural domain dynamics which may include domain swapping and dimerization to form a 5,6-domain-swapped dimer. The observed structural changes in the receptor when pindolol, the partial agonist, was docked were midway between those observed for propranolol and norepinephrine. These structural changes, particularly the changes in helix-helix interactions at the dimer interface, support the idea that the receptors have a very dynamic structure and may shed some light on the activation process. The receptor model used in these studies is well supported by experiment, includingsite-directed mutagenesis (helices 1-7), zinc binding studies (helices 2, 3, 5, and 6), the substituted cysteine accessibility method (helices 3, 5, and 7), and site-directed spin-labeling studies (helices 3-6).

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 00:34:53