Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
CCK-B/gastrin receptor transmembrane domain mutations selectively alter synthetic agonist efficacy without affecting the activity of endogenous peptides
Autore:
Blaker, M; Ren, Y; Seshadri, L; McBride, EW; Beinborn, M; Kopin, AS;
Indirizzi:
New England Med Ctr, Tupper Res Inst, Dept Med, Boston, MA 02111 USA New England Med Ctr Boston MA USA 02111 t, Dept Med, Boston, MA 02111 USA New England Med Ctr, Tupper Res Inst, GRASP Digest Dis Ctr, Boston, MA 02111 USA New England Med Ctr Boston MA USA 02111 est Dis Ctr, Boston, MA 02111 USA
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 2, volume: 58, anno: 2000,
pagine: 399 - 406
SICI:
0026-895X(200008)58:2<399:CRTDMS>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
BINDING-SITE CREVICE; PROTEIN-COUPLED RECEPTORS; MEMBRANE-SPANNING SEGMENT; DOPAMINE D2 RECEPTOR; CHOLECYSTOKININ-B RECEPTOR; AMINO-ACID; BETA(2)-ADRENERGIC RECEPTOR; CONSTITUTIVE ACTIVATION; FUNCTIONAL-PROPERTIES; ANTAGONISTS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Kopin, AS New England Med Ctr, Tupper Res Inst, Dept Med, Box 239,750 Washington St,Boston, MA 02111 USA New England Med Ctr Box 239,750 Washington St Boston MA USA 02111
Citazione:
M. Blaker et al., "CCK-B/gastrin receptor transmembrane domain mutations selectively alter synthetic agonist efficacy without affecting the activity of endogenous peptides", MOLEC PHARM, 58(2), 2000, pp. 399-406

Abstract

Recent efforts have focused on identifying small nonpeptide molecules thatcan mimic the activity of endogenous peptide hormones. Understanding the molecular basis of ligand-induced receptor activation by these divergent classes of ligands should expedite the process of drug development. Using the cholecystokinin-B/gastrin receptor (CCK-BR) as a model system, we have recently shown that both affinity and efficacy of nonpeptide ligands are markedly affected by amino acid alterations within a putative transmembrane domain (TMD) ligand pocket. In this report, we examine whether residues projecting into the TMD pocket determine the pharmacologic properties of structurally diverse CCK-BR ligands, including peptides and synthetic peptide-derivedpartial agonists (peptoids). Nineteen mutant human CCK-BRs, each includinga single TMD amino acid substitution, were transiently expressed in COS-7 cells and characterized. Binding affinities as well as ligand-induced inositol phosphate production at the mutant CCK-BRs were assessed for peptides (CCK-8 and CCK-4) and for peptoids (PD-135,158 and PD-136,450). Distinct as well as overlapping determinants of peptide and peptoid binding affinity were identified, supporting that both classes of ligands, at least in part, interact with the CCK-BR TMD ligand pocket. Eight point mutations resulted in marked increases or decreases in the functional activity of the syntheticpeptoid ligands. In contrast, the functional activity of both peptides, CCK-8 and CCK-4, was not affected by any of the CCK-BR mutations. These findings suggest that the mechanisms underlying activation of G-protein-coupled receptors by endogenous peptide hormones versus synthetic ligands may markedly differ.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 07:27:09