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Characterization of GABA binding site in GABA-Br1 receptor shed some light on the activation mechanism of the GABA-B receptor

Characterization of GABA binding site in GABA-Br1 receptor shed some light on the activation mechanism of the GABA-B receptor

Society for Neuroscience Abstracts 26(1-2): Abstract No -622 16

One characteristic feature of family 3 GPCRs (mGlu, CaS, GABA-B receptors) is their large extracellular domain which share a similar structure with bacterial periplasmic amino acid binding proteins, like the leucine binding protein (LBP). These proteins are constituted of two lobes which close upon ligand binding. Accordingly, it has been proposed that the agonists of family 3 GPCRs stabilize a closed state of the LBP-like domain which in turn activates the 7TM region. In order to further understand the activation mechanism of these receptors, we characterized the agonist binding site of the GABA-B1-R using site directed mutagenesis and modeling studies. Our data show that GABA binds in lobe-I, its carboxylic group interacting with the side chain of a Ser via H-bonds, and its amino group forming and ionic interaction with an Asp residue. Baclofen was found to interact the same way in lobe-I, but its chlorophenyl group was found to fit in a network of hydrophobic residues of lobe-II in a 3D model of the closed form of the receptor. Interestingly, the disruption of this hydrophobic network converts baclofen from agonist to an antagonist. These data support the idea that the stabilization of the closed state of the LBP-like domain of family 3 GPCR is a prerequisite for their activation.

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