ISSN:
1399-0047
Source:
Crystallography Journals Online : IUCR Backfile Archive 1948-2001
Topics:
Chemistry and Pharmacology
,
Geosciences
,
Physics
Notes:
The crystal structures of two anionic inhibitor complexes of human carbonic anhydrase I (HCAI), namely, HCAI–iodide and HCAI–Au(CN)2−, have been refined by the restrained least-squares method at 2.2 and 2 Å nominal resolution, respectively, with good stereochemistry for the final models. The R values have improved from 30.3 to 16.6% for HCAI–iodide and from 28.8 to 17.1% for HCAI–Au(CN)2−. The sites of inhibitor binding as elucidated are totally different in the two structures. The iodide anion replaces the zinc-bound H2O/OH− ligand and renders the enzyme inactive. This result confirms that the zinc-bound H2O/OH− is the activity-linked group in carbonic anhydrase enzymes. Au(CN)2− binds at a different and new site near the zinc ion, without liganding to the metal. The N atom of Au(CN)2− is within hydrogen-bonding distance of the zinc-bound H2O/OH− group which shifts by about 0.4 Å away from the zinc ion in relation to its position in the native HCAI. It is proposed that the presence of the inhibitor Au(CN)2− results in a conformational reorientation of the activity-linked group, due to hydrogen-bond formation with the inhibitor, which in turn sterically hinders the binding of the substrate CO2 molecule in the active site, leading to the inhibition of HCAI enzyme.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1107/S0907444994001873
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