Study of interaction between agonists and asn293 in helix VI of human
beta(2)-adrenergic receptor
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..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.