Abstract
The crystal structures of sulfanilamide (4-aminobenzene-sulfonamide) complexed to the enzyme variant human carbonic anhydrase I Michigan 1 (CA I M1) and to its (Zn)2 adduct refined at 2.2 and 2.6 Å resolution respectively are described. Comparisons among these structures and the corresponding sulfonamide adduct of human CA I show significant differences in the orientation of the inhibitor molecule and in its interactions with active site residues such as His200, Thr199, Leu198, Gln92, and Arg/His67 which are known to play important roles in substrate or inhibitor recognition and binding. In CA I M1 molecule B a lengthening of the Zn-N1 sulfanilamide bond distance and a corresponding shortening of the distance between the sulfonamido group and Thr199 are observed compared with the values for native CA I. When the second Zn(II) ion is present in the active site, the p-amino group and the aromatic ring of the inhibitor molecule appear to tilt towards Gln92 and Arg67, moving away from residues His200 and Leu198. The structural differences in inhibitor binding between the CA I isozyme and the CA I M1 variant are discussed in terms of the different inhibition constants measured for a variety of aromatic and heterocyclic sulfonamides.
Published Version
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