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Vol. 56, Issue 2, 448-454, August 1999
-Aminobutyric AcidB
Receptors Is Sufficient to Specify Agonist and Antagonist Binding
Novartis Pharma AG, Nervous System Research, Basel, Switzerland
(B.M., C.S., M.K., J.H., W.F., J.M., R.K., K.K., B.B.); Bristol
University, Department of Anatomy, Medical School, Bristol, United
Kingdom (M.K., J.H.); and Centre National de la Recherche Scientifique,
Mécanismes Moléculaires des Communications Cellulaires,
Montpellier, France (C.J., J.-P.P.)
The recently identified 
-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.
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