title: Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase.
abstract: The X-ray crystal structure for the adduct of human carbonic anhydrase II (hCA II) with estrone-3-O-sulfamate (EMATE), an antiendocrine agent showing both CA and estrone sulfatase inhibitory properties, has been resolved at a resolution of 1.5A. Its binding to the enzyme is similar to that of other sulfamates/sulfonamides, considering the interactions of the zinc anchoring group, but differs considerably when the steroidal scaffold of the inhibitor is analyzed. This part of the inhibitor interacts only within the hydrophobic half of the CA active site, interacting with residues Val 121, Phe 131, Val 135 and Pro 202, and leaving the hydrophilic half able to accommodate several water molecules not present in the uncomplexed enzyme. In addition, a very short bond of 1.78A between the zinc ion and the coordinated nitrogen atom of the sulfamate moiety is observed, which may explain the high affinity of this inhibitor for hCA II (K(i) of 10nM).
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, Rm. 188, I-50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Abbate
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Montero
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray / Q000379:methods; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; C088768:estrone-3-O-sulfamate; D004970:Estrone; D043266:Steryl-Sulfatase; D024402:Carbonic Anhydrase II