6qn0: Difference between revisions
New page: '''Unreleased structure''' The entry 6qn0 is ON HOLD Authors: Dvinskis, E., Leitans, J., Tars, K. Description: Three dimensional structure of human carbonic anhydrase XII in complex wi... |
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The | ==Three dimensional structure of human carbonic anhydrase XII in complex with benzenesulfonamide== | ||
<StructureSection load='6qn0' size='340' side='right'caption='[[6qn0]], [[Resolution|resolution]] 1.89Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6qn0]] 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=6QN0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QN0 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.89Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J8Q:~{N}-butyl-4-chloranyl-2-(2-phenylethylsulfanyl)-5-sulfamoyl-benzamide'>J8Q</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6qn0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qn0 OCA], [https://pdbe.org/6qn0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qn0 RCSB], [https://www.ebi.ac.uk/pdbsum/6qn0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qn0 ProSAT]</span></td></tr> | |||
</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 == | |||
By applying an approach of a "ring with two tails", a series of novel inhibitors possessing high-affinity and significant selectivity towards selected carbonic anhydrase (CA) isoforms has been designed. The "ring" consists of 2-chloro/bromo-benzenesulfonamide, where the sulfonamide group is as an anchor coordinating the Zn(II) in the active site of CAs, and halogen atom orients the ring affecting the affinity and selectivity. First "tail" is a substituent containing carbonyl, carboxyl, hydroxyl, ether groups or hydrophilic amide linkage. The second "tail" contains aryl- or alkyl-substituents attached through a sulfanyl or sulfonyl group. Both "tails" are connected to the benzene ring and play a crucial role in selectivity. Varying the substituents, we designed compounds selective for CA VII, CA IX, CA XII, or CA XIV. Since due to binding-linked protonation reactions the binding-ready fractions of the compound and protein are much lower than one, the "intrinsic" affinities were calculated that should be used to study correlations between crystal structures and the thermodynamics of binding for rational drug design. The "intrinsic" affinities together with the intrinsic enthalpies and entropies of binding together with co-crystal structures were used demonstrate structural factors determining major contributions for compound affinity and selectivity. | |||
Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms.,Zaksauskas A, Capkauskaite E, Jezepcikas L, Linkuviene V, Paketuryte V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Manakova E, Grazulis S, Tars K, Matulis D Eur J Med Chem. 2020 Jan 1;185:111825. doi: 10.1016/j.ejmech.2019.111825. Epub, 2019 Oct 31. PMID:31740053<ref>PMID:31740053</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Dvinskis | <div class="pdbe-citations 6qn0" style="background-color:#fffaf0;"></div> | ||
[[Category: Leitans | |||
[[Category: Tars | ==See Also== | ||
*[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Dvinskis E]] | |||
[[Category: Leitans J]] | |||
[[Category: Tars K]] | |||
Latest revision as of 15:04, 24 January 2024
Three dimensional structure of human carbonic anhydrase XII in complex with benzenesulfonamideThree dimensional structure of human carbonic anhydrase XII in complex with benzenesulfonamide
Structural highlights
DiseaseCAH12_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] FunctionCAH12_HUMAN Reversible hydration of carbon dioxide. Publication Abstract from PubMedBy applying an approach of a "ring with two tails", a series of novel inhibitors possessing high-affinity and significant selectivity towards selected carbonic anhydrase (CA) isoforms has been designed. The "ring" consists of 2-chloro/bromo-benzenesulfonamide, where the sulfonamide group is as an anchor coordinating the Zn(II) in the active site of CAs, and halogen atom orients the ring affecting the affinity and selectivity. First "tail" is a substituent containing carbonyl, carboxyl, hydroxyl, ether groups or hydrophilic amide linkage. The second "tail" contains aryl- or alkyl-substituents attached through a sulfanyl or sulfonyl group. Both "tails" are connected to the benzene ring and play a crucial role in selectivity. Varying the substituents, we designed compounds selective for CA VII, CA IX, CA XII, or CA XIV. Since due to binding-linked protonation reactions the binding-ready fractions of the compound and protein are much lower than one, the "intrinsic" affinities were calculated that should be used to study correlations between crystal structures and the thermodynamics of binding for rational drug design. The "intrinsic" affinities together with the intrinsic enthalpies and entropies of binding together with co-crystal structures were used demonstrate structural factors determining major contributions for compound affinity and selectivity. Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms.,Zaksauskas A, Capkauskaite E, Jezepcikas L, Linkuviene V, Paketuryte V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Manakova E, Grazulis S, Tars K, Matulis D Eur J Med Chem. 2020 Jan 1;185:111825. doi: 10.1016/j.ejmech.2019.111825. Epub, 2019 Oct 31. PMID:31740053[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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