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A tight coupling between ??Y97 and ??F200 of the GABA(A) receptor mediates GABA binding.


ABSTRACT: The GABA(A) receptor is an oligopentameric chloride channel that is activated via conformation changes induced upon the binding of the endogenous ligand, GABA, to the extracellular inter-subunit interfaces. Although dozens of amino acid residues at the ?/? interface have been implicated in ligand binding, the structural elements that mediate ligand binding and receptor activation are not yet fully described. In this study, double-mutant cycle analysis was employed to test for possible interactions between several arginines (??R67, ??R120, ??R132, and ??R207) and two aromatic residues (??Y97 and ??F200) that are present in the ligand-binding pocket and are known to influence GABA affinity. Our results show that neither ??R67 nor ??R120 is functionally coupled to either of the aromatics, whereas a moderate coupling exists between ??R132 and both aromatic residues. Significant functional coupling between ??R207 and both ??Y97 and ??F200 was found. Furthermore, we identified an even stronger coupling between the two aromatics, ??Y97 and ??F200, and for the first time provided direct evidence for the involvement of ??Y97 and ??F200 in GABA binding. As these residues are tightly linked, and mutation of either has similar, severe effects on GABA binding and receptor kinetics, we believe they form a single functional unit that may directly coordinate GABA.

SUBMITTER: Tran PN 

PROVIDER: S-EPMC3190653 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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A tight coupling between β₂Y97 and β₂F200 of the GABA(A) receptor mediates GABA binding.

Tran Phu N PN   Laha Kurt T KT   Wagner David A DA  

Journal of neurochemistry 20110831 2


The GABA(A) receptor is an oligopentameric chloride channel that is activated via conformation changes induced upon the binding of the endogenous ligand, GABA, to the extracellular inter-subunit interfaces. Although dozens of amino acid residues at the α/β interface have been implicated in ligand binding, the structural elements that mediate ligand binding and receptor activation are not yet fully described. In this study, double-mutant cycle analysis was employed to test for possible interactio  ...[more]

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