Abstract
Site-directed mutation of serine 110 (Ser(3.35)) and serine 114 (Ser(3.39)) in the human melatonin MT1, receptor to alanine residues reduced ligand binding affinities of seven known melatonin receptor agonists and partial agonists by 3- to 15-fold. These mutants also displayed a relative reduction in their affinities for melatonin-mediated functional responses of 30- and 14-fold, respectively. In contrast to the observed effects of the agonists and partial agonists, the melatonin receptor antagonist luzindole was found to bind to mutants Ser(3.35)Ala and Ser(3.39)Ala with affinities equivalent to that determined for the wild-type melatonin MT1 receptor. Luzindole was subsequently confirmed as an antagonist of melatonin-mediated functional responses for both mutant receptors. These studies have identified that in the human melatonin MT1 receptor, Ser(3.35) and Ser(3.39), in transmembrane domain 3, are critical for the formation of the high-affinity ligand binding site for agonists and partial agonists but not for the antagonist luzindole. (C) 2001 Academic Press.
| Original language | English |
|---|---|
| Pages (from-to) | 1229-1236 |
| Number of pages | 8 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 282 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 20 Apr 2001 |
Keywords
- melatonin
- MT1 receptor
- agonist
- antagonist
- ligand binding
- transmembrane domain 3
- G protein-coupled receptor
- site-directed mutagenesis
- beta-adrenergic-receptor
- protein-coupled receptors
- ovine pars tuberalis
- ligand-binding
- human MEL(1A)
- cloning
- identification
- inhibition
- subtypes
- roles
Cite this
Serine residues 110 and 114 are required for agonist binding but not antagonist binding to the melatonin MT1 receptor. / Conway, S ; Mowat, E S ; Drew, Janice; Barrett, Perry; Delagrange, P ; Morgan, Peter John.
In: Biochemical and Biophysical Research Communications, Vol. 282, No. 5, 20.04.2001, p. 1229-1236.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Serine residues 110 and 114 are required for agonist binding but not antagonist binding to the melatonin MT1 receptor
AU - Conway, S
AU - Mowat, E S
AU - Drew, Janice
AU - Barrett, Perry
AU - Delagrange, P
AU - Morgan, Peter John
PY - 2001/4/20
Y1 - 2001/4/20
N2 - Site-directed mutation of serine 110 (Ser(3.35)) and serine 114 (Ser(3.39)) in the human melatonin MT1, receptor to alanine residues reduced ligand binding affinities of seven known melatonin receptor agonists and partial agonists by 3- to 15-fold. These mutants also displayed a relative reduction in their affinities for melatonin-mediated functional responses of 30- and 14-fold, respectively. In contrast to the observed effects of the agonists and partial agonists, the melatonin receptor antagonist luzindole was found to bind to mutants Ser(3.35)Ala and Ser(3.39)Ala with affinities equivalent to that determined for the wild-type melatonin MT1 receptor. Luzindole was subsequently confirmed as an antagonist of melatonin-mediated functional responses for both mutant receptors. These studies have identified that in the human melatonin MT1 receptor, Ser(3.35) and Ser(3.39), in transmembrane domain 3, are critical for the formation of the high-affinity ligand binding site for agonists and partial agonists but not for the antagonist luzindole. (C) 2001 Academic Press.
AB - Site-directed mutation of serine 110 (Ser(3.35)) and serine 114 (Ser(3.39)) in the human melatonin MT1, receptor to alanine residues reduced ligand binding affinities of seven known melatonin receptor agonists and partial agonists by 3- to 15-fold. These mutants also displayed a relative reduction in their affinities for melatonin-mediated functional responses of 30- and 14-fold, respectively. In contrast to the observed effects of the agonists and partial agonists, the melatonin receptor antagonist luzindole was found to bind to mutants Ser(3.35)Ala and Ser(3.39)Ala with affinities equivalent to that determined for the wild-type melatonin MT1 receptor. Luzindole was subsequently confirmed as an antagonist of melatonin-mediated functional responses for both mutant receptors. These studies have identified that in the human melatonin MT1 receptor, Ser(3.35) and Ser(3.39), in transmembrane domain 3, are critical for the formation of the high-affinity ligand binding site for agonists and partial agonists but not for the antagonist luzindole. (C) 2001 Academic Press.
KW - melatonin
KW - MT1 receptor
KW - agonist
KW - antagonist
KW - ligand binding
KW - transmembrane domain 3
KW - G protein-coupled receptor
KW - site-directed mutagenesis
KW - beta-adrenergic-receptor
KW - protein-coupled receptors
KW - ovine pars tuberalis
KW - ligand-binding
KW - human MEL(1A)
KW - cloning
KW - identification
KW - inhibition
KW - subtypes
KW - roles
U2 - 10.1006/bbrc.2001.4722
DO - 10.1006/bbrc.2001.4722
M3 - Article
VL - 282
SP - 1229
EP - 1236
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 5
ER -