Beta(1)-selective agonist (-)-1-(3,4-dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(-)-RO363] differentially interacts with key amino acids responsible for beta(1)-selective binding in resting and active states.
Détails
ID Serval
serval:BIB_63FB506C8037
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Beta(1)-selective agonist (-)-1-(3,4-dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(-)-RO363] differentially interacts with key amino acids responsible for beta(1)-selective binding in resting and active states.
Périodique
Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565
Statut éditorial
Publié
Date de publication
2002
Peer-reviewed
Oui
Volume
301
Numéro
1
Pages
51-58
Langue
anglais
Notes
Publication types: Journal Article
Résumé
(-)-1-(3,4-Dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(-)-RO363] is a highly selective beta(1)-adrenergic receptor (beta(1)AR) agonist. To study the binding site of beta(1)-selective agonist, chimeric beta(1)/beta(2)ARs and Ala-substituted beta(1)ARs were constructed. Several key residues of beta(1)AR [Leu(110) and Thr(117) in transmembrane domain (TMD) 2], and Phe(359) in TMD 7] were found to be responsible for beta(1)-selective binding of (-)-RO363, as determined by competitive binding. Based on these results, we built a three-dimensional model of the binding domain for (-)-RO363. The model indicated that TMD 2 and TMD 7 of beta(1)AR form a binding pocket; the methoxyphenyl group of N-substituent of (-)-RO363 seems to locate within the cavity surrounded by Leu(110), Thr(117), and Phe(359). The amino acids Leu(110) and Phe(359) interact with the phenyl ring of (-)-RO363, whereas Thr(117) forms hydrogen bond with the methoxy group of (-)-RO363. To examine the interaction of these residues with beta(1)AR in an active state, each of the amino acids was changed to Ala in a constitutively active (CA)-beta(1)AR mutant. The degree of decrease in the affinity of CA-beta(1)AR for (-)-RO363 was essentially the same as that of wild-type beta(1)AR when mutated at Leu(110) and Thr(117). However, the affinity was decreased in Ala-substituted mutant of Phe(359) compared with that of wild-type beta(1)AR. These results indicated that Leu(110) and Thr(117) are necessary for the initial binding of (-)-RO363 with beta(1)-selectivity, and interaction of Phe(359) with the N-substituent of (-)-RO363 in an active state is stronger than in the resting state.
Mots-clé
Adrenergic beta-Agonists, Amino Acid Sequence, Amino Acids, Catechols, Gene Expression Regulation, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Mutation, Plasmids, Propanolamines, Radioligand Assay, Receptors, Adrenergic, beta-1, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins
Pubmed
Web of science
Création de la notice
24/01/2008 12:05
Dernière modification de la notice
20/08/2019 15:20