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Vol. 53, Issue 5, 870-877, May 1998
1
1 
-Aminobutyric AcidA Receptors
Center for Molecular Recognition (J.H., M.H.A.) and the Departments
of
Physiology and Cellular Biophysics (J.H., M.H.A.) and
Medicine
(M.H.A.), Columbia University, New York, New York 10032
Zn2+ inhibits currents through 
-aminobutyric acid
(GABA)A receptors. Its affinity depends on the subunit
composition; 
1
1 receptors are inhibited with high affinity
(IC50 = 0.54 µM). We sought to identify the
residues that form this high affinity Zn2+ binding site.
1His267 aligns with 1Ser272, a residue near the extracellular end
of the M2 membrane-spanning segment that we previously demonstrated to
be exposed in the channel. The Zn2+ affinity of 11
H267S was reduced by 300-fold (IC50 = 161 µM). Addition of a histidine at the aligned position in
1 creates a receptor, 1S272H1, that should have five
channel-lining histidines; the Zn2+ affinity was increased
20-fold (IC50 = 0.025 µM). Shifting the position of the histidine from the 1 subunit to the aligned position in 1 with the two mutants 1S272H1H267S reduced the affinity (IC50 = 26 µM) compared with wild-type. We
infer that the high affinity Zn2+ binding site involves
1His267 from at least two subunits. For two histidines to interact
with a Zn2+ ion, the carbons must be separated by <13
Å. This limits the separation of the subunits and provides a
constraint on the possible quaternary structures of the channel. The
ability of a divalent cation to penetrate from the extracellular end of
the channel to 1His267 implies that the charge-selectivity filter,
the structure that discriminates between anions and cations, is located
at a more cytoplasmic position than 1His267; this is consistent with our previous work that showed that positively charged
sulfhydryl-specific reagents reacted with an engineered cysteine
residue as cytoplasmic as 1T261C.
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