First Crystal Structures of Human Carbonic Anhydrase II in Complex with Dual Aromatase−Steroid Sulfatase Inhibitors
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...
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Veröffentlicht in: | Biochemistry (Easton) 2005-05, Vol.44 (18), p.6858-6866 |
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creator | Lloyd, Matthew D Thiyagarajan, Nethaji Ho, Yaik T Woo, L. W. Lawrence Sutcliffe, Oliver B Purohit, Atul Reed, Michael J Acharya, K. Ravi Potter, Barry V. L |
description | 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 Å, 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. |
doi_str_mv | 10.1021/bi047692e |
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W. Lawrence ; Sutcliffe, Oliver B ; Purohit, Atul ; Reed, Michael J ; Acharya, K. Ravi ; Potter, Barry V. L</creator><creatorcontrib>Lloyd, Matthew D ; Thiyagarajan, Nethaji ; Ho, Yaik T ; Woo, L. W. Lawrence ; Sutcliffe, Oliver B ; Purohit, Atul ; Reed, Michael J ; Acharya, K. Ravi ; Potter, Barry V. L</creatorcontrib><description>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 Å, 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.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi047692e</identifier><identifier>PMID: 15865431</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Aromatase Inhibitors - chemistry ; Aromatase Inhibitors - metabolism ; Binding Sites ; Carbonic Anhydrase II - antagonists & inhibitors ; Carbonic Anhydrase II - chemistry ; Carbonic Anhydrase II - metabolism ; Crystallization ; Crystallography, X-Ray ; Dimethyl Sulfoxide - chemistry ; Drug Stability ; Enzyme Stability ; Estrone - analogs & derivatives ; Estrone - chemistry ; Estrone - metabolism ; Humans ; Ligands ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Solvents ; Steryl-Sulfatase - antagonists & inhibitors ; Steryl-Sulfatase - chemistry ; Steryl-Sulfatase - metabolism</subject><ispartof>Biochemistry (Easton), 2005-05, Vol.44 (18), p.6858-6866</ispartof><rights>Copyright © 2005 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a351t-ba2b63f8e150f0c3b0d76065a3fbc10ff68c9f8262b0adce4e5762ed11c6cacf3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/bi047692e$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bi047692e$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15865431$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lloyd, Matthew D</creatorcontrib><creatorcontrib>Thiyagarajan, Nethaji</creatorcontrib><creatorcontrib>Ho, Yaik T</creatorcontrib><creatorcontrib>Woo, L. W. Lawrence</creatorcontrib><creatorcontrib>Sutcliffe, Oliver B</creatorcontrib><creatorcontrib>Purohit, Atul</creatorcontrib><creatorcontrib>Reed, Michael J</creatorcontrib><creatorcontrib>Acharya, K. Ravi</creatorcontrib><creatorcontrib>Potter, Barry V. L</creatorcontrib><title>First Crystal Structures of Human Carbonic Anhydrase II in Complex with Dual Aromatase−Steroid Sulfatase Inhibitors</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>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 Å, 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.</description><subject>Aromatase Inhibitors - chemistry</subject><subject>Aromatase Inhibitors - metabolism</subject><subject>Binding Sites</subject><subject>Carbonic Anhydrase II - antagonists & inhibitors</subject><subject>Carbonic Anhydrase II - chemistry</subject><subject>Carbonic Anhydrase II - metabolism</subject><subject>Crystallization</subject><subject>Crystallography, X-Ray</subject><subject>Dimethyl Sulfoxide - chemistry</subject><subject>Drug Stability</subject><subject>Enzyme Stability</subject><subject>Estrone - analogs & derivatives</subject><subject>Estrone - chemistry</subject><subject>Estrone - metabolism</subject><subject>Humans</subject><subject>Ligands</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>Solvents</subject><subject>Steryl-Sulfatase - antagonists & inhibitors</subject><subject>Steryl-Sulfatase - chemistry</subject><subject>Steryl-Sulfatase - metabolism</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0M1u1DAQB3ALgei2cOAFkC8g9ZB2nMR2ctymtF2pKkhbzpbj2FqXJF78IbpvwJlH5Ekw3VW5cBp55ucZ6Y_QOwJnBEpy3luoOWtL_QItCC2hqNuWvkQLAGBF2TI4QschPORnDbx-jY4IbRitK7JA6cr6EHHndyHKEa-jTyomrwN2Bt-kSc64k753s1V4OW92g5dB49UK2zxw03bUj_iHjRt8mfL3pXeTjFn8_vlrHbV3dsDrNJqnHl7NG9vb6Hx4g14ZOQb99lBP0NerT_fdTXH7-XrVLW8LWVESi16WPatMowkFA6rqYeAMGJWV6RUBY1ijWtOUrOxBDkrXmnJW6oEQxZRUpjpBH_d7t959TzpEMdmg9DjKWbsUBOO84TXnGZ7uofIuBK-N2Ho7Sb8TBMTfjMVzxtm-PyxN_aSHf_IQagbFHtgQ9ePzXPpv-WDFqbj_shacXHbXd3AhIPsPey9VEA8u-Tln8p_DfwAXSJSy</recordid><startdate>20050510</startdate><enddate>20050510</enddate><creator>Lloyd, Matthew D</creator><creator>Thiyagarajan, Nethaji</creator><creator>Ho, Yaik T</creator><creator>Woo, L. W. Lawrence</creator><creator>Sutcliffe, Oliver B</creator><creator>Purohit, Atul</creator><creator>Reed, Michael J</creator><creator>Acharya, K. Ravi</creator><creator>Potter, Barry V. L</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20050510</creationdate><title>First Crystal Structures of Human Carbonic Anhydrase II in Complex with Dual Aromatase−Steroid Sulfatase Inhibitors</title><author>Lloyd, Matthew D ; Thiyagarajan, Nethaji ; Ho, Yaik T ; Woo, L. W. Lawrence ; Sutcliffe, Oliver B ; Purohit, Atul ; Reed, Michael J ; Acharya, K. Ravi ; Potter, Barry V. L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a351t-ba2b63f8e150f0c3b0d76065a3fbc10ff68c9f8262b0adce4e5762ed11c6cacf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Aromatase Inhibitors - chemistry</topic><topic>Aromatase Inhibitors - metabolism</topic><topic>Binding Sites</topic><topic>Carbonic Anhydrase II - antagonists & inhibitors</topic><topic>Carbonic Anhydrase II - chemistry</topic><topic>Carbonic Anhydrase II - metabolism</topic><topic>Crystallization</topic><topic>Crystallography, X-Ray</topic><topic>Dimethyl Sulfoxide - chemistry</topic><topic>Drug Stability</topic><topic>Enzyme Stability</topic><topic>Estrone - analogs & derivatives</topic><topic>Estrone - chemistry</topic><topic>Estrone - metabolism</topic><topic>Humans</topic><topic>Ligands</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - metabolism</topic><topic>Solvents</topic><topic>Steryl-Sulfatase - antagonists & inhibitors</topic><topic>Steryl-Sulfatase - chemistry</topic><topic>Steryl-Sulfatase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lloyd, Matthew D</creatorcontrib><creatorcontrib>Thiyagarajan, Nethaji</creatorcontrib><creatorcontrib>Ho, Yaik T</creatorcontrib><creatorcontrib>Woo, L. W. Lawrence</creatorcontrib><creatorcontrib>Sutcliffe, Oliver B</creatorcontrib><creatorcontrib>Purohit, Atul</creatorcontrib><creatorcontrib>Reed, Michael J</creatorcontrib><creatorcontrib>Acharya, K. Ravi</creatorcontrib><creatorcontrib>Potter, Barry V. L</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lloyd, Matthew D</au><au>Thiyagarajan, Nethaji</au><au>Ho, Yaik T</au><au>Woo, L. W. Lawrence</au><au>Sutcliffe, Oliver B</au><au>Purohit, Atul</au><au>Reed, Michael J</au><au>Acharya, K. Ravi</au><au>Potter, Barry V. L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>First Crystal Structures of Human Carbonic Anhydrase II in Complex with Dual Aromatase−Steroid Sulfatase Inhibitors</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2005-05-10</date><risdate>2005</risdate><volume>44</volume><issue>18</issue><spage>6858</spage><epage>6866</epage><pages>6858-6866</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>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 Å, 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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>15865431</pmid><doi>10.1021/bi047692e</doi><tpages>9</tpages></addata></record> |
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subjects | Aromatase Inhibitors - chemistry Aromatase Inhibitors - metabolism Binding Sites Carbonic Anhydrase II - antagonists & inhibitors Carbonic Anhydrase II - chemistry Carbonic Anhydrase II - metabolism Crystallization Crystallography, X-Ray Dimethyl Sulfoxide - chemistry Drug Stability Enzyme Stability Estrone - analogs & derivatives Estrone - chemistry Estrone - metabolism Humans Ligands Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - chemistry Recombinant Proteins - metabolism Solvents Steryl-Sulfatase - antagonists & inhibitors Steryl-Sulfatase - chemistry Steryl-Sulfatase - metabolism |
title | First Crystal Structures of Human Carbonic Anhydrase II in Complex with Dual Aromatase−Steroid Sulfatase Inhibitors |
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