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 Å (1 Å = 0.1 nm) to the final crystallographic R and Rfree 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 lengthyco-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.
Crystal structure of human carbonic anhydrase II complexed with ananti-convulsant sugar sulphamate
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Rosario RECACHA, Michael J. COSTANZO, Bruce E. MARYANOFF, Debasish CHATTOPADHYAY; Crystal structure of human carbonic anhydrase II complexed with ananti-convulsant sugar sulphamate. Biochem J 1 February 2002; 361 (3): 437–441. doi: https://doi.org/10.1042/bj3610437
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