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| | ==Crystal structure of catalytic domain of human carbonic anhydrase isozyme XII with inhibitor== | | ==Crystal structure of catalytic domain of human carbonic anhydrase isozyme XII with inhibitor== |
| - | <StructureSection load='4qj0' size='340' side='right' caption='[[4qj0]], [[Resolution|resolution]] 1.55Å' scene=''> | + | <StructureSection load='4qj0' size='340' side='right'caption='[[4qj0]], [[Resolution|resolution]] 1.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qj0]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QJ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QJ0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qj0]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QJ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QJ0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=WWX:2,3,6-TRIFLUORO-5-{[(1R,2S)-2-HYDROXY-1,2-DIPHENYLETHYL]AMINO}-4-[(2-HYDROXYETHYL)SULFONYL]BENZENESULFONAMIDE'>WWX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qiy|4qiy]], [[4qiz|4qiz]], [[4qjm|4qjm]], [[4qjo|4qjo]], [[4qjp|4qjp]], [[4qjw|4qjw]], [[4qjx|4qjx]], [[4qtl|4qtl]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=WWX:2,3,6-TRIFLUORO-5-{[(1R,2S)-2-HYDROXY-1,2-DIPHENYLETHYL]AMINO}-4-[(2-HYDROXYETHYL)SULFONYL]BENZENESULFONAMIDE'>WWX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </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=4qj0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qj0 OCA], [https://pdbe.org/4qj0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qj0 RCSB], [https://www.ebi.ac.uk/pdbsum/4qj0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qj0 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qj0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qj0 OCA], [http://pdbe.org/4qj0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qj0 RCSB], [http://www.ebi.ac.uk/pdbsum/4qj0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qj0 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CAH12_HUMAN CAH12_HUMAN]] Defects in CA12 are the cause of hyperchlorhidrosis isolated (HCHLH) [MIM:[http://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> | + | [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 == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CAH12_HUMAN CAH12_HUMAN]] Reversible hydration of carbon dioxide. | + | [https://www.uniprot.org/uniprot/CAH12_HUMAN CAH12_HUMAN] Reversible hydration of carbon dioxide. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4qj0" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4qj0" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Carbonate dehydratase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Grazulis, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Manakova, E]] | + | [[Category: Grazulis S]] |
| - | [[Category: Smirnov, A]] | + | [[Category: Manakova E]] |
| - | [[Category: Benzenesulfonamide]] | + | [[Category: Smirnov A]] |
| - | [[Category: Carbonic anhydrase]]
| + | |
| - | [[Category: Drug design]]
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| - | [[Category: Lyase-lyase inhibitor complex]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| 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 PubMed
Substituted tri- and tetrafluorobenzenesulfonamides were designed, synthesized, and evaluated as high-affinity and isoform-selective carbonic anhydrase (CA) inhibitors. Their binding affinities for recombinant human CA I, II, VA, VI, VII, XII, and XIII catalytic domains were determined by fluorescent thermal shift assay, isothermal titration calorimetry, and a stopped-flow CO2 hydration assay. Variation of the substituents at the 2-, 3-, and 4-positions yielded compounds with a broad range of binding affinities and isoform selectivities. Several 2,4-substituted-3,5,6-trifluorobenzenesulfonamides were effective CA XIII inhibitors with high selectivity over off-target CA I and CA II. 3,4-Disubstituted-2,5,6-trifluorobenzenesulfonamides bound CAs with higher affinity than 2,4-disubstituted-3,5,6-trifluorobenzenesulfonamides. Many such fluorinated benzenesulfonamides were found to be nanomolar inhibitors of CA II, CA VII, tumor-associated CA IX and CA XII, and CA XIII. X-ray crystal structures of inhibitors bound in the active sites of several CA isoforms provide structure-activity relationship information for inhibitor binding affinities and selectivity.
Functionalization of Fluorinated Benzenesulfonamides and Their Inhibitory Properties toward Carbonic Anhydrases.,Dudutiene V, Zubriene A, Smirnov A, Timm DD, Smirnoviene J, Kazokaite J, Michailoviene V, Zaksauskas A, Manakova E, Grazulis S, Matulis D ChemMedChem. 2015 Apr;10(4):662-87. doi: 10.1002/cmdc.201402490. Epub 2015 Mar, 10. PMID:25758852[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Feldshtein M, Elkrinawi S, Yerushalmi B, Marcus B, Vullo D, Romi H, Ofir R, Landau D, Sivan S, Supuran CT, Birk OS. Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII. Am J Hum Genet. 2010 Nov 12;87(5):713-20. doi: 10.1016/j.ajhg.2010.10.008. Epub, 2010 Oct 28. PMID:21035102 doi:10.1016/j.ajhg.2010.10.008
- ↑ Dudutiene V, Zubriene A, Smirnov A, Timm DD, Smirnoviene J, Kazokaite J, Michailoviene V, Zaksauskas A, Manakova E, Grazulis S, Matulis D. Functionalization of Fluorinated Benzenesulfonamides and Their Inhibitory Properties toward Carbonic Anhydrases. ChemMedChem. 2015 Apr;10(4):662-87. doi: 10.1002/cmdc.201402490. Epub 2015 Mar, 10. PMID:25758852 doi:http://dx.doi.org/10.1002/cmdc.201402490
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