Insights into the structural basis for zinc inhibition of the glycine receptor

Abstract

Histidines 107 and 109 in the glycine receptor (GlyR) α1 subunit have previously been identified as determinants of the inhibitory zinc-binding site. Based on modeling of the GlyR α1 subunit extracellular domain by homology to the acetylcholine-binding protein crystal structure, we hypothesized that inhibitory zinc is bound within the vestibule lumen at subunit interfaces, where it is ligated by His107 from one subunit and His109 from an adjacent subunit. This was tested by co-expressing α1 subunits containing the H107A mutation with α1 subunits containing the H109A mutation. Although sensitivity to zinc inhibition is markedly reduced when either mutation is individually incorporated into al..