Abstract
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.
Footnotes
- Received April 1, 1999.
- Accepted May 7, 1999.
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Send reprint requests to: Dr. Bernhard Bettler, Novartis Pharma AG, K-125.6.08, Nervous System Research, CH-4002 Basel, Switzerland. E-mail:bernhard.bettler{at}pharma.novartis.com
- The American Society for Pharmacology and Experimental Therapeutics
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