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==Crystal structure of carbonic anhydrase XII with methyl 2-chloro-4-[(2-phenylethyl)sulfanyl]-5-sulfamoylbenzoate== | ==Crystal structure of carbonic anhydrase XII with methyl 2-chloro-4-[(2-phenylethyl)sulfanyl]-5-sulfamoylbenzoate== | ||
<StructureSection load='7puw' size='340' side='right'caption='[[7puw]]' scene=''> | <StructureSection load='7puw' size='340' side='right'caption='[[7puw]], [[Resolution|resolution]] 1.42Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PUW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PUW FirstGlance]. <br> | <table><tr><td colspan='2'>[[7puw]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PUW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PUW FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7puw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7puw OCA], [https://pdbe.org/7puw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7puw RCSB], [https://www.ebi.ac.uk/pdbsum/7puw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7puw ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=84I:methyl+2-chloranyl-4-(2-phenylethylsulfanyl)-5-sulfamoyl-benzoate'>84I</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7puu|7puu]], [[7puv|7puv]]</div></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7puw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7puw OCA], [https://pdbe.org/7puw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7puw RCSB], [https://www.ebi.ac.uk/pdbsum/7puw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7puw ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://www.uniprot.org/uniprot/CAH12_HUMAN CAH12_HUMAN]] Defects in CA12 are the cause of hyperchlorhidrosis isolated (HCHLH) [MIM:[https://omim.org/entry/143860 143860]]. HCHLH is a disorder characterized by excessive sweating and increased sweat chloride levels. Affected individuals suffer from episodes of hyponatremic dehydration and report increased amounts of visible salt precipitates in sweat.<ref>PMID:21035102</ref> | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/CAH12_HUMAN CAH12_HUMAN]] Reversible hydration of carbon dioxide. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes. | |||
Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX.,Zaksauskas A, Capkauskaite E, Paketuryte-Latve V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Stancaitis L, Mickeviciute A, Jachno J, Jezepcikas L, Linkuviene V, Sakalauskas A, Manakova E, Grazulis S, Matuliene J, Tars K, Matulis D Int J Mol Sci. 2021 Dec 23;23(1). pii: ijms23010130. doi: 10.3390/ijms23010130. PMID:35008553<ref>PMID:35008553</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7puw" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Carbonate dehydratase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Grazulis S]] | [[Category: Grazulis, S]] | ||
[[Category: Manakova E]] | [[Category: Manakova, E]] | ||
[[Category: Smirnov A]] | [[Category: Smirnov, A]] | ||
[[Category: Benzenesulfonamide]] | |||
[[Category: Carbonic anhydrase]] | |||
[[Category: Drug design]] | |||
[[Category: Lyase]] | |||
[[Category: Lyase-lyase inhibitor complex]] | |||
[[Category: Metal-binding]] | |||
Revision as of 10:11, 27 January 2022
Crystal structure of carbonic anhydrase XII with methyl 2-chloro-4-[(2-phenylethyl)sulfanyl]-5-sulfamoylbenzoateCrystal structure of carbonic anhydrase XII with methyl 2-chloro-4-[(2-phenylethyl)sulfanyl]-5-sulfamoylbenzoate
Structural highlights
Disease[CAH12_HUMAN] Defects in CA12 are the cause of hyperchlorhidrosis isolated (HCHLH) [MIM:143860]. HCHLH is a disorder characterized by excessive sweating and increased sweat chloride levels. Affected individuals suffer from episodes of hyponatremic dehydration and report increased amounts of visible salt precipitates in sweat.[1] Function[CAH12_HUMAN] Reversible hydration of carbon dioxide. Publication Abstract from PubMedAmong the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes. Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX.,Zaksauskas A, Capkauskaite E, Paketuryte-Latve V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Stancaitis L, Mickeviciute A, Jachno J, Jezepcikas L, Linkuviene V, Sakalauskas A, Manakova E, Grazulis S, Matuliene J, Tars K, Matulis D Int J Mol Sci. 2021 Dec 23;23(1). pii: ijms23010130. doi: 10.3390/ijms23010130. PMID:35008553[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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