title: Crystal structure of human carbonic anhydrase II complexed with an anti-convulsant sugar sulphamate.
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.
authors.affiliation: Center for Biophysical Sciences and Engineering, and School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Rosario
authors.initials: R
authors.lastname: Recacha
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Costanzo
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Debasish
authors.initials: D
authors.lastname: Chattopadhyay
mesh_terms: D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004583:Electrons; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D013431:Sulfates; D013451:Sulfonic Acids / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D008024:Ligands; C448988:RWJ 37497; D013431:Sulfates; D013451:Sulfonic Acids; D005632:Fructose; C005741:sulfamic acid; D024402:Carbonic Anhydrase II; D010100:Oxygen