PMID- 10531390
OWN - NLM
STAT- MEDLINE
DCOM- 19991124
LR  - 20190607
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 56
IP  - 5
DP  - 1999 Nov
TI  - Binding pockets of the beta(1)- and beta(2)-adrenergic receptors for 
      subtype-selective agonists.
PG  - 875-85
AB  - We examined the subtype-selective binding site of the beta-adrenergic receptors 
      (betaARs). The beta(1)/beta(2)-chimeric receptors showed the importance of the 
      second and seventh transmembrane domains (TM2 and TM7) of the beta(2)AR for the 
      binding of the beta(2)-selective agonists such as formoterol and procaterol. 
      Alanine-substituted mutants of TM7 of the beta(2)AR showed that Tyr(308,) located 
      at the top of TM7, mainly contributed to beta(2) selectivity. However, Tyr(308) 
      interacted with formoterol and procaterol in two different ways. The results of 
      Ala- and Phe-substituted mutants indicated that the phenyl group of Tyr(308) 
      interacted with the phenyl group in the N-substituent of formoterol (hydrophobic 
      interaction), and the hydroxyl group of Tyr(308) interacted with the protonated 
      amine of procaterol (hydrophilic interaction). In contrast to beta(2)AR, TM2 is a 
      major determinant that beta(1)-selective agonists such as denopamine and T-0509 
      bound the beta(1)AR with high affinity. Three amino acids (Leu(110), Thr(117), 
      and Val(120)) in TM2 of the beta(1)AR were identified as major determinants for 
      beta(1)-selective binding of these agonists. Three-dimensional models built on 
      the basis of the predicted structure of rhodopsin showed that Tyr(308) of the 
      beta(2)AR covered the binding pocket formed by TM2 and TM7 from the upper side, 
      and Thr(117) of the beta(1)AR located in the middle of the binding pocket to 
      provide a hydrogen bonding for the beta(1)-selective agonists. These data 
      indicate that TM2 and TM7 of the betaAR formed the binding pocket that binds the 
      betaAR subtype-selective agonists with high affinity.
FAU - Isogaya, M
AU  - Isogaya M
AD  - Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical 
      Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
FAU - Sugimoto, Y
AU  - Sugimoto Y
FAU - Tanimura, R
AU  - Tanimura R
FAU - Tanaka, R
AU  - Tanaka R
FAU - Kikkawa, H
AU  - Kikkawa H
FAU - Nagao, T
AU  - Nagao T
FAU - Kurose, H
AU  - Kurose H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Adrenergic beta-1 Receptor Agonists)
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Adrenergic beta-Agonists)
RN  - 0 (Adrenergic beta-Antagonists)
RN  - 0 (Ethanolamines)
RN  - 0 (Propanolamines)
RN  - 0 (Receptors, Adrenergic, beta-1)
RN  - 0 (Receptors, Adrenergic, beta-2)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 60979-28-4 (IPS 339)
RN  - 75241-20-2 (RP333)
RN  - 7HE0JQL703 (Xamoterol)
RN  - 9Y8NXQ24VQ (Propranolol)
RN  - OF5P57N2ZX (Alanine)
RN  - QF8SVZ843E (Albuterol)
RN  - V5F60UPD8P (denopamine)
RN  - W34SHF8J2K (Formoterol Fumarate)
RN  - X4W3ENH1CV (Norepinephrine)
RN  - X7I3EMM5K0 (Procaterol)
SB  - IM
MH  - *Adrenergic beta-1 Receptor Agonists
MH  - *Adrenergic beta-2 Receptor Agonists
MH  - Adrenergic beta-Agonists/*metabolism
MH  - Adrenergic beta-Antagonists/metabolism
MH  - Alanine/genetics/metabolism
MH  - Albuterol/metabolism/pharmacology
MH  - Amino Acid Substitution
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Computer Simulation
MH  - Ethanolamines/metabolism/pharmacology
MH  - Formoterol Fumarate
MH  - Humans
MH  - Models, Molecular
MH  - Norepinephrine/pharmacology
MH  - Procaterol/metabolism/pharmacology
MH  - Propanolamines/pharmacology
MH  - Propranolol/pharmacology
MH  - Receptors, Adrenergic, beta-1/metabolism
MH  - Receptors, Adrenergic, beta-2/genetics/metabolism
MH  - Recombinant Fusion Proteins/agonists/metabolism
MH  - Xamoterol/pharmacology
EDAT- 1999/10/26 00:00
MHDA- 1999/10/26 00:01
CRDT- 1999/10/26 00:00
PHST- 1999/10/26 00:00 [pubmed]
PHST- 1999/10/26 00:01 [medline]
PHST- 1999/10/26 00:00 [entrez]
AID - 10.1124/mol.56.5.875 [doi]
PST - ppublish
SO  - Mol Pharmacol. 1999 Nov;56(5):875-85. doi: 10.1124/mol.56.5.875.