Molecular mechanisms of sweet receptor function.
نویسندگان
چکیده
The T1R taste receptors, like other type 3 G-protein-coupled receptors (GPCRs), have a large amino terminal extracellular domain. Type 3 GPCRs typically function as dimers, but each monomer can independently bind ligand. Based on studies with the metabotropic glutamate receptors (mGluRs) the site for ligand binding in type 3 GPCRs is thought to be in a shell-like cleft formed by two lobes within the extracellular domain. Occupation of the binding cleft and binding to both of the lobes allows the ‘shells’ to close and stabilizes the active conformation of the receptor (Kunishima et al., 2000; Jingami et al., 2003). T1R2 + T1R3 monomers form a heterodimeric receptor that is responsive to sweet tasting molecules (unpublished results; Nelson et al., 2001). Small molecule sweeteners can occupy the receptor’s extracellular cleft, however, protein sweeteners (e.g. brazzein, monellin and thaumatin) are much too large to fit within this cavity. We hypothesized that these sweet proteins extend ‘fingers’ into the cleft to occupy the small-molecule binding site. Using the crystal structure of mGluR1 (Kunishima et al., 2000) to model the extracellular domains of human T1R2 (hT1R2) + hT1R3, we attempted to dock brazzein into the closed cleft of hT1R2. We then mutated residues within the T1R2 to see if they disrupted the response of the expressed receptor to sweeteners.
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ورودعنوان ژورنال:
- Chemical senses
دوره 30 Suppl 1 شماره
صفحات -
تاریخ انتشار 2005