1xq0
From Proteopedia
(New page: 200px<br /> <applet load="1xq0" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xq0, resolution 1.76Å" /> '''Structure of human ...) |
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| - | [[Image:1xq0.gif|left|200px]]<br /> | + | [[Image:1xq0.gif|left|200px]]<br /><applet load="1xq0" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1xq0" size=" | + | |
caption="1xq0, resolution 1.76Å" /> | caption="1xq0, resolution 1.76Å" /> | ||
'''Structure of human carbonic anhydrase II with 4-[(3-bromo-4-O-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]-triazole'''<br /> | '''Structure of human carbonic anhydrase II with 4-[(3-bromo-4-O-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]-triazole'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Carbonic anhydrase (CA) catalyzes the reversible hydration of carbon | + | 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. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XQ0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN and 4TR as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] Full crystallographic information is available from [http:// | + | 1XQ0 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=4TR:'>4TR</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XQ0 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Acharya, K | + | [[Category: Acharya, K R.]] |
| - | [[Category: Ho, Y | + | [[Category: Ho, Y T.]] |
| - | [[Category: Lloyd, M | + | [[Category: Lloyd, M D.]] |
| - | [[Category: Potter, B | + | [[Category: Potter, B V.L.]] |
[[Category: Purohit, A.]] | [[Category: Purohit, A.]] | ||
| - | [[Category: Reed, M | + | [[Category: Reed, M J.]] |
| - | [[Category: Sutcliffe, O | + | [[Category: Sutcliffe, O B.]] |
[[Category: Thiyagarajan, N.]] | [[Category: Thiyagarajan, N.]] | ||
| - | [[Category: Woo, L | + | [[Category: Woo, L W.L.]] |
[[Category: 4TR]] | [[Category: 4TR]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
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[[Category: dual aromatase-steroid sulfatase inhibitor (dasi)]] | [[Category: dual aromatase-steroid sulfatase inhibitor (dasi)]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:57:25 2008'' |
Revision as of 13:57, 21 February 2008
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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
Contents |
Overview
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.
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 with and as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 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 Thu Feb 21 15:57:25 2008
Categories: Carbonate dehydratase | Homo sapiens | Single protein | Acharya, K R. | Ho, Y T. | Lloyd, M D. | Potter, B V.L. | Purohit, A. | Reed, M J. | Sutcliffe, O B. | Thiyagarajan, N. | Woo, L W.L. | 4TR | ZN | Anti-cancer drug delivery | Carbonic anhydrase | Dual aromatase-steroid sulfatase inhibitor (dasi)
