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
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
Auteur(s)
Sugimoto Y., Fujisawa R., Tanimura R., Lattion A.L., Cotecchia S., Tsujimoto G., Nagao T., Kurose H.
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 11:05
Dernière modification de la notice
20/08/2019 14:20
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