TY - JOUR T1 - The N-Terminal Domain of γ-Aminobutyric Acid<sub>B</sub>Receptors Is Sufficient to Specify Agonist and Antagonist Binding JF - Molecular Pharmacology JO - Mol Pharmacol SP - 448 LP - 454 DO - 10.1124/mol.56.2.448 VL - 56 IS - 2 AU - Barbara Malitschek AU - Claude Schweizer AU - Miranda Keir AU - Jakob Heid AU - Wolfgang Froestl AU - Johannes Mosbacher AU - Rainer Kuhn AU - Jeremy Henley AU - Cécile Joly AU - Jean-Phillippe Pin AU - Klemens Kaupmann AU - Bernhard Bettler Y1 - 1999/08/01 UR - http://molpharm.aspetjournals.org/content/56/2/448.abstract N2 - The recently identified γ-aminobutyric acid type B receptors (GABABRs) share low sequence similarity with the metabotropic glutamate (mGlu) receptors. Like the mGlu receptors, the N-terminal extracellular domain (NTED) of GABABRs is proposed to be related to bacterial periplasmic binding proteins (PBPs). However, in contrast to the mGlu receptors, the GABABRs lack a cysteine-rich region that links the PBP-like domain to the first transmembrane domain. This cysteine-rich region is necessary for the PBP-like domain of mGlu receptors to bind glutamate. To delimit the ligand-binding domain of GABABRs, we constructed a series of chimeric GABABR1/mGluR1 and truncated GABABR1 receptor mutants. We provide evidence that despite the lack of a cysteine-rich region, the NTED of GABABRs contains all of the structural information that is necessary and sufficient for ligand binding. Moreover, a soluble protein corresponding to the NTED of GABABRs reproduces the binding pharmacology of wild-type receptors. This demonstrates that the ligand-binding domain of the GABABRs can correctly fold when dissociated from the transmembrane domains. ER -