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Titolo:
REPLACEMENT OF GLN(280) BY HIS IN TM6 OF THE HUMAN ORL1 RECEPTOR INCREASES AFFINITY BUT REDUCES INTRINSIC ACTIVITY OF OPIOIDS
Autore:
MOLLEREAU C; MOISAND C; BUTOUR JL; PARMENTIER M; MEUNIER JC;
Indirizzi:
INST PHARMACOL & BIOL STRUCT,CNRS UPR 9062,205 ROUTE NARBONNE F-31077TOULOUSE FRANCE FREE UNIV BRUSSELS,IRIBHN B-1070 BRUSSELS BELGIUM
Titolo Testata:
FEBS letters
fascicolo: 1, volume: 395, anno: 1996,
pagine: 17 - 21
SICI:
0014-5793(1996)395:1<17:ROGBHI>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-COUPLED RECEPTOR; OPIATE-RECEPTOR; GENE FAMILY; MOLECULAR-CLONING; TISSUE DISTRIBUTION; CDNA CLONING; MEMBER; LOCALIZATION; SELECTIVITY; EXPRESSION;
Keywords:
OPIOID RECEPTOR; NOCICEPTIN/ORPHANIN FQ; SITE-DIRECTED MUTAGENESIS; AGONIST/ANTAGONIST BINDING; ADENYLATE CYCLASE INHIBITION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
26
Recensione:
Indirizzi per estratti:
Citazione:
C. Mollereau et al., "REPLACEMENT OF GLN(280) BY HIS IN TM6 OF THE HUMAN ORL1 RECEPTOR INCREASES AFFINITY BUT REDUCES INTRINSIC ACTIVITY OF OPIOIDS", FEBS letters, 395(1), 1996, pp. 17-21

Abstract

The ORL1 (Opioid Receptor-Like) receptor is the G protein-coupled receptor whose amino acid sequence is closest to those of opioid receptors, Residues that are conserved in ORL1 and the three types of opioid receptor, but also a residue, His in the sixth putative transmembrane (TM6) helix, which is present in all opioid receptor types but absent in ORL1, appear to play a key role in receptor recognition and/or activation, Here we have sought to create an opioid binding pocket in the non-opioid ORL1 receptor by replacing residue Gln(280) in its TM6 by the corresponding His residue of opioid receptors, The mutation affects neither the affinity of nociceptin - the natural ORL1 agonist - for the receptor, nor the potency of nociceptin to inhibit adenylyl cyclase via ORL1, In contrast, we find that a few opioid ligands, the agonistslofentanil, etorphine and dynorphin A, and especially the antagonistsdiprenorphine and nor-BNI, bind the mutant Q280H receptor with substantially (5- to > 100-fold) higher apparent affinity than they do the wild-type receptor, Moreover, lofentanil and etorphine no longer act aspure agonists, as they do at the native ORL1 receptor. but are endowed with clear antagonist properties at the mutant receptor, The mutation Q280H, which increases affinity while decreasing intrinsic activity of opioids at ORL1, emphasizes the importance of the His residue for opioid recognition and activation.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/07/20 alle ore 08:55:00