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| | <StructureSection load='6g7a' size='340' side='right'caption='[[6g7a]], [[Resolution|resolution]] 1.42Å' scene=''> | | <StructureSection load='6g7a' size='340' side='right'caption='[[6g7a]], [[Resolution|resolution]] 1.42Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6g7a]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G7A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G7A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6g7a]] 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=6G7A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G7A 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=EOQ:4-chloranyl-~{N}-(2-hydroxyethyl)-2-[(phenylmethyl)amino]-5-sulfamoyl-benzamide'>EOQ</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]] 1.42Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6g5l|6g5l]], [[6g5u|6g5u]], [[6g6t|6g6t]]</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=EOQ:4-chloranyl-~{N}-(2-hydroxyethyl)-2-[(phenylmethyl)amino]-5-sulfamoyl-benzamide'>EOQ</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=6g7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g7a OCA], [https://pdbe.org/6g7a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g7a RCSB], [https://www.ebi.ac.uk/pdbsum/6g7a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g7a 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=6g7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g7a OCA], [http://pdbe.org/6g7a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g7a RCSB], [http://www.ebi.ac.uk/pdbsum/6g7a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g7a 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 6g7a" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6g7a" 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: 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 comple]]
| + | |
| - | [[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
Rational design of compounds that would bind specific pockets of the target proteins is a difficult task in drug design. The 12 isoforms of catalytically active human carbonic anhydrases (CAs) have highly similar active sites that make it difficult to design inhibitors selective for one or several CA isoforms. A series of CA inhibitors based on 2-chloro/bromo-benzenesulfonamide that is largely fixed in the CA active site together with one or two tails yielded compounds that were synthesized and evaluated as inhibitors of CA isoforms. Introduction of a second tail had significant influence on the binding affinity and two-tailed compounds in most cases provided high affinity and selectivity for CA IX and CA XIV. The contacts between several compounds and CA amino acids were determined by X-ray crystallography. Together with the intrinsic enthalpy and entropy of binding they provided the structure-thermodynamics correlations for this series of compounds with the insight how to rationally build compounds with desired CA isoform as a target.
Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases.,Zaksauskas A, Capkauskaite E, Jezepcikas L, Linkuviene V, Kisonaite M, Smirnov A, Manakova E, Grazulis S, Matulis D Eur J Med Chem. 2018 Aug 5;156:61-78. doi: 10.1016/j.ejmech.2018.06.059. Epub, 2018 Jun 27. PMID:30006175[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
- ↑ Zaksauskas A, Capkauskaite E, Jezepcikas L, Linkuviene V, Kisonaite M, Smirnov A, Manakova E, Grazulis S, Matulis D. Design of two-tail compounds with rotationally fixed benzenesulfonamide ring as inhibitors of carbonic anhydrases. Eur J Med Chem. 2018 Aug 5;156:61-78. doi: 10.1016/j.ejmech.2018.06.059. Epub, 2018 Jun 27. PMID:30006175 doi:http://dx.doi.org/10.1016/j.ejmech.2018.06.059
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