Study of interaction between agonists and asn293 in helix VI of human
beta(2)-adrenergic receptor
H. Zuurmond, J. Hessling, K. Bluml, M. Lohse, und A. Ijzerman. Mol Pharmacol, 56 (5):
909-16(November 1999)Zuurmond, H M Hessling, J Bluml, K Lohse, M Ijzerman, A P Research
Support, Non-U.S. Gov't United states Molecular pharmacology Mol
Pharmacol. 1999 Nov;56(5):909-16..
Zusammenfassung
Previously, we demonstrated the involvement of Asn293 in helix VI
of the human beta(2)-adrenergic receptor in stereoselective agonist
recognition and activation. In the present study, we have further
explored the role of this residue by synthesizing derivatives of
isoproterenol and clenbuterol, two beta-adrenergic receptor agonists.
We analyzed their efficacy and affinity on the wild-type and a mutant
receptor (Asn293Leu). Each compound had similar efficacy (tau values)
on both the wild-type and mutant receptor, although tau values varied
considerably among the eight compounds studied. It appeared that
one derivative of isoproterenol, but not of clenbuterol, showed a
gain in affinity from the wild type to the mutant receptor. This
derivative had a methyl substituent instead of the usual beta-OH
group in the aliphatic side chain of isoproterenol, compatible with
the more lipophilic nature of the leucine side chain. Such a "gain
of function" approach through a combination of synthetic chemistry
with molecular biology, may be useful to enhance our insight into
the precise atomic events that govern ligand-receptor interactions.
Zuurmond, H M Hessling, J Bluml, K Lohse, M Ijzerman, A P Research
Support, Non-U.S. Gov't United states Molecular pharmacology Mol
Pharmacol. 1999 Nov;56(5):909-16.
%0 Journal Article
%1 Zuurmond1999
%A Zuurmond, H. M.
%A Hessling, J.
%A Bluml, K.
%A Lohse, M.
%A Ijzerman, A. P.
%D 1999
%J Mol Pharmacol
%K & Adrenergic Animals Asparagine/*metabolism Binding, CHO Clenbuterol/analogs Competitive Cricetinae Humans Isoproterenol/analogs Ligands Models, Molecular Protein Secondary Spectrophotometry, Structure, Ultraviolet beta-2/chemistry/genetics/*metabolism beta-Agonists/chemical derivatives/chemical synthesis/*pharmacology synthesis/pharmacology Receptor Cell
%N 5
%P 909-16
%T Study of interaction between agonists and asn293 in helix VI of human
beta(2)-adrenergic receptor
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10531394
%V 56
%X Previously, we demonstrated the involvement of Asn293 in helix VI
of the human beta(2)-adrenergic receptor in stereoselective agonist
recognition and activation. In the present study, we have further
explored the role of this residue by synthesizing derivatives of
isoproterenol and clenbuterol, two beta-adrenergic receptor agonists.
We analyzed their efficacy and affinity on the wild-type and a mutant
receptor (Asn293Leu). Each compound had similar efficacy (tau values)
on both the wild-type and mutant receptor, although tau values varied
considerably among the eight compounds studied. It appeared that
one derivative of isoproterenol, but not of clenbuterol, showed a
gain in affinity from the wild type to the mutant receptor. This
derivative had a methyl substituent instead of the usual beta-OH
group in the aliphatic side chain of isoproterenol, compatible with
the more lipophilic nature of the leucine side chain. Such a "gain
of function" approach through a combination of synthetic chemistry
with molecular biology, may be useful to enhance our insight into
the precise atomic events that govern ligand-receptor interactions.
@article{Zuurmond1999,
abstract = {Previously, we demonstrated the involvement of Asn293 in helix VI
of the human beta(2)-adrenergic receptor in stereoselective agonist
recognition and activation. In the present study, we have further
explored the role of this residue by synthesizing derivatives of
isoproterenol and clenbuterol, two beta-adrenergic receptor agonists.
We analyzed their efficacy and affinity on the wild-type and a mutant
receptor (Asn293Leu). Each compound had similar efficacy (tau values)
on both the wild-type and mutant receptor, although tau values varied
considerably among the eight compounds studied. It appeared that
one derivative of isoproterenol, but not of clenbuterol, showed a
gain in affinity from the wild type to the mutant receptor. This
derivative had a methyl substituent instead of the usual beta-OH
group in the aliphatic side chain of isoproterenol, compatible with
the more lipophilic nature of the leucine side chain. Such a "gain
of function" approach through a combination of synthetic chemistry
with molecular biology, may be useful to enhance our insight into
the precise atomic events that govern ligand-receptor interactions.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Zuurmond, H. M. and Hessling, J. and Bluml, K. and Lohse, M. and Ijzerman, A. P.},
biburl = {https://www.bibsonomy.org/bibtex/223c89b4ff5ab237ab8d7e5e175b0f088/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {0d7a67551faa90e844d443fb3dc43d9a},
intrahash = {23c89b4ff5ab237ab8d7e5e175b0f088},
issn = {0026-895X (Print) 0026-895X (Linking)},
journal = {Mol Pharmacol},
keywords = {& Adrenergic Animals Asparagine/*metabolism Binding, CHO Clenbuterol/analogs Competitive Cricetinae Humans Isoproterenol/analogs Ligands Models, Molecular Protein Secondary Spectrophotometry, Structure, Ultraviolet beta-2/chemistry/genetics/*metabolism beta-Agonists/chemical derivatives/chemical synthesis/*pharmacology synthesis/pharmacology Receptor Cell},
month = Nov,
note = {Zuurmond, H M Hessling, J Bluml, K Lohse, M Ijzerman, A P Research
Support, Non-U.S. Gov't United states Molecular pharmacology Mol
Pharmacol. 1999 Nov;56(5):909-16.},
number = 5,
pages = {909-16},
shorttitle = {Study of interaction between agonists and asn293 in helix VI of human
beta(2)-adrenergic receptor},
timestamp = {2010-12-14T18:22:43.000+0100},
title = {Study of interaction between agonists and asn293 in helix VI of human
beta(2)-adrenergic receptor},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10531394},
volume = 56,
year = 1999
}