6t5q: Difference between revisions
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==Human Carbonic anhydrase XII bound by 3,5-diphenylbenzenesulfonamide== | ==Human Carbonic anhydrase XII bound by 3,5-diphenylbenzenesulfonamide== | ||
<StructureSection load='6t5q' size='340' side='right'caption='[[6t5q]]' scene=''> | <StructureSection load='6t5q' size='340' side='right'caption='[[6t5q]], [[Resolution|resolution]] 1.80Å' 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=6T5Q OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6T5Q FirstGlance]. <br> | <table><tr><td colspan='2'>[[6t5q]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T5Q OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6T5Q FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6t5q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t5q OCA], [http://pdbe.org/6t5q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t5q RCSB], [http://www.ebi.ac.uk/pdbsum/6t5q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t5q 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MKQ:3,5-diphenylbenzenesulfonamide'>MKQ</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">[[6t4n|6t4n]], [[6t4o|6t4o]], [[6t4p|6t4p]], [[6t5c|6t5c]], [[6t5p|6t5p]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CA12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://proteopedia.org/fgij/fg.htm?mol=6t5q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t5q OCA], [http://pdbe.org/6t5q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t5q RCSB], [http://www.ebi.ac.uk/pdbsum/6t5q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t5q ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== 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> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/CAH12_HUMAN CAH12_HUMAN]] Reversible hydration of carbon dioxide. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In the design of high-affinity and enzyme isoform-selective inhibitors, we applied an approach of augmenting the substituents attached to the benzenesulfonamide scaffold in three ways, namely, substitutions at the 3,5- or 2,4,6-positions or expansion of the condensed ring system. The increased size of the substituents determined the spatial limitations of the active sites of the 12 catalytically active human carbonic anhydrase (CA) isoforms until no binding was observed because of the inability of the compounds to fit in the active site. This approach led to the discovery of high-affinity and high-selectivity compounds for the anticancer target CA IX and antiobesity target CA VB. The x-ray crystallographic structures of compounds bound to CA IX showed the positions of the bound compounds, whereas computational modeling confirmed that steric clashes prevent the binding of these compounds to other isoforms and thus avoid undesired side effects. Such an approach, based on the Lock-and-Key principle, could be used for the development of enzyme-specific drug candidate compounds. | |||
Isoform-Selective Enzyme Inhibitors by Exploring Pocket Size According to the Lock-and-Key Principle.,Dudutiene V, Zubriene A, Kairys V, Smirnov A, Smirnoviene J, Leitans J, Kazaks A, Tars K, Manakova L, Grazulis S, Matulis D Biophys J. 2020 Sep 9. pii: S0006-3495(20)30688-3. doi:, 10.1016/j.bpj.2020.08.037. PMID:32971003<ref>PMID:32971003</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6t5q" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Carbonate dehydratase]] | |||
[[Category: Human]] | |||
[[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 23:46, 28 October 2020
Human Carbonic anhydrase XII bound by 3,5-diphenylbenzenesulfonamideHuman Carbonic anhydrase XII bound by 3,5-diphenylbenzenesulfonamide
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 PubMedIn the design of high-affinity and enzyme isoform-selective inhibitors, we applied an approach of augmenting the substituents attached to the benzenesulfonamide scaffold in three ways, namely, substitutions at the 3,5- or 2,4,6-positions or expansion of the condensed ring system. The increased size of the substituents determined the spatial limitations of the active sites of the 12 catalytically active human carbonic anhydrase (CA) isoforms until no binding was observed because of the inability of the compounds to fit in the active site. This approach led to the discovery of high-affinity and high-selectivity compounds for the anticancer target CA IX and antiobesity target CA VB. The x-ray crystallographic structures of compounds bound to CA IX showed the positions of the bound compounds, whereas computational modeling confirmed that steric clashes prevent the binding of these compounds to other isoforms and thus avoid undesired side effects. Such an approach, based on the Lock-and-Key principle, could be used for the development of enzyme-specific drug candidate compounds. Isoform-Selective Enzyme Inhibitors by Exploring Pocket Size According to the Lock-and-Key Principle.,Dudutiene V, Zubriene A, Kairys V, Smirnov A, Smirnoviene J, Leitans J, Kazaks A, Tars K, Manakova L, Grazulis S, Matulis D Biophys J. 2020 Sep 9. pii: S0006-3495(20)30688-3. doi:, 10.1016/j.bpj.2020.08.037. PMID:32971003[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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