RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 448
OP 454
DO 10.1124/mol.56.2.448
VO 56
IS 2
A1 Malitschek, Barbara
A1 Schweizer, Claude
A1 Keir, Miranda
A1 Heid, Jakob
A1 Froestl, Wolfgang
A1 Mosbacher, Johannes
A1 Kuhn, Rainer
A1 Henley, Jeremy
A1 Joly, Cécile
A1 Pin, Jean-Phillippe
A1 Kaupmann, Klemens
A1 Bettler, Bernhard
YR 1999
UL http://molpharm.aspetjournals.org/content/56/2/448.abstract
AB 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.