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.
|Number of pages||8|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 20 Apr 2001|
- MT1 receptor
- ligand binding
- transmembrane domain 3
- G protein-coupled receptor
- site-directed mutagenesis
- protein-coupled receptors
- ovine pars tuberalis
- human MEL(1A)
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From melatonin receptors to Valdoxan
Peter Morgan (Coordinator), Lynda Williams (Coordinator), Perry Barrett (Coordinator) & A D Strosberg (Coordinator)
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