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| | {{STRUCTURE_1xq0| PDB=1xq0 | SCENE= }} | | {{STRUCTURE_1xq0| PDB=1xq0 | SCENE= }} |
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| - | '''Structure of human carbonic anhydrase II with 4-[(3-bromo-4-O-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]-triazole'''
| + | ===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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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_15865431}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15865431 is the PubMed ID number. |
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| | ==Disease== | | ==Disease== |
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| | [[Category: Anti-cancer drug delivery]] | | [[Category: Anti-cancer drug delivery]] |
| | [[Category: Carbonic anhydrase]] | | [[Category: Carbonic anhydrase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 15:21:18 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 11:09:59 2008'' |
Revision as of 08:10, 28 July 2008
Template:STRUCTURE 1xq0
Structure of human carbonic anhydrase II with 4-[(3-bromo-4-O-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]-triazole
Template:ABSTRACT PUBMED 15865431
Disease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this Structure
1XQ0 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Jul 28 11:09:59 2008
