1xq0
Structure of human carbonic anhydrase II with 4-[(3-bromo-4-O-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]-triazole
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OverviewOverview
Carbonic anhydrase (CA) catalyzes the reversible hydration of carbon, dioxide to hydrogen carbonate. The role of CA in maintaining pH balance, has made it an attractive drug target for the treatment of cancer, and it, has recently been implicated in the delivery of sulfamate-containing, drugs. With the acceptance of steroid sulfatase as a target for, hormone-dependent cancer, novel dual aromatase-steroid sulfatase, inhibitors (DASIs) containing a sulfamate group are now being developed., In this study, we show that CA II is potently inhibited by several members, of this class of inhibitor. The structures of CA II complexed with, 4-[(4-O-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole (K(D) =, 84 +/- 5 nM) and, 4-[(3-bromo-4-O-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole, (K(D) = 454 +/- 29 nM) are reported to 2.02 and 1.76 A, respectively. Both, inhibitors ligate to the active site zinc(II) atom via their sulfamate, nitrogen, while the rest of the molecule is contained within the, hydrophobic binding pocket. Key protein residues include Val-121, Phe-131, Val-135, Val-143, Leu-141, Leu-198, Pro-202, and Leu-204. Despite being, structurally similar, the two ligands experience different types of, binding particularly in the sulfamate-containing aromatic ring and the, opposite geometric arrangement of the triazole and cyanophenyl groups, around the configurationally invertible central nitrogen atom. Small, changes in inhibitor structure can cause large changes in binding to CA, II, and this underlines the importance of structure-based drug design with, this enzyme and other isoforms relevant to potential anticancer therapy., Moreover, these results underpin the idea that binding to erythrocyte CA, II may be a general method of stabilizing and delivering sulfamate-based, drugs in vivo.
DiseaseDisease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this StructureAbout this Structure
1XQ0 is a Single protein structure of sequence from Homo sapiens with ZN and 4TR as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
ReferenceReference
First crystal structures of human carbonic anhydrase II in complex with dual aromatase-steroid sulfatase inhibitors., Lloyd MD, Thiyagarajan N, Ho YT, Woo LW, Sutcliffe OB, Purohit A, Reed MJ, Acharya KR, Potter BV, Biochemistry. 2005 May 10;44(18):6858-66. PMID:15865431
Page seeded by OCA on Mon Nov 12 20:09:28 2007