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. 2002 Feb 1;361(Pt 3):437–441. doi: 10.1042/0264-6021:3610437

Crystal structure of human carbonic anhydrase II complexed with an anti-convulsant sugar sulphamate.

Rosario Recacha 1, Michael J Costanzo 1, Bruce E Maryanoff 1, Debasish Chattopadhyay 1
PMCID: PMC1222325  PMID: 11802772

Abstract

The fructose-based sugar sulphamate RWJ-37497, a potent analogue of the widely used anti-epileptic drug topiramate, possesses anti-convulsant and carbonic anhydrase-inhibitory activities. We have studied the binding interactions of RWJ-37497 in the active site of human carbonic anhydrase II by X-ray crystallography. The atomic positions of the enzyme inhibitor complex were refined at a resolution of 2.1 A (1 A=0.1 nm) to the final crystallographic R and R(free) values of 0.18 and 0.23, respectively. The inhibitor co-ordinates to the active-site zinc ion through its oxygen atom and the ionized nitrogen atom of the sulphamate group by replacing the metal-bound water molecules, although the sulphamoyl oxygen atom provides a rather lengthy co-ordination. The 4,5-cyclic sulphate group is positioned in a hydrophobic pocket of the active site, making contacts with the residues Phe-131, Leu-198, Pro-201 and Pro-202. Since the ligand was found to be intact, concerns about RWJ-37947 irreversibly alkylating the enzyme through its 4,5-cyclic sulphate group were dispelled.

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Selected References

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