View source for 9fn7


==Crystal structure of human carboanhydrase XII with 5,7,8-trifluoro-4-(3-propylhexyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide 1,1-dioxide==
<StructureSection load='9fn7' size='340' side='right'caption='[[9fn7]], [[Resolution|resolution]] 1.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9fn7]] 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=9FN7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FN7 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]] 1.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1ID0:5,7,8-tris(fluoranyl)-1,1-bis(oxidanylidene)-4-(3-propylhexyl)-2,3-dihydro-1$l^{6},4-benzothiazine-6-sulfonamide'>A1ID0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=9fn7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fn7 OCA], [https://pdbe.org/9fn7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fn7 RCSB], [https://www.ebi.ac.uk/pdbsum/9fn7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fn7 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 ==
High affinity and selectivity for intended targets is an important goal of small molecule design in drug discovery, yet balancing molecular flexibility and rigidity remains a challenge. While flexible compounds can increase target affinity, they often result in non-specific interactions and reduced selectivity. In contrast, rigid compounds may recognize their target more precisely and have lower off-target effects. In this study, we incorporated a 1,1-dioxido-1,4-thiazine ring into fluorinated benzenesulfonamide derivatives with bulky meta-substituents to enhance selectivity for human carbonic anhydrase IX (CAIX), an important cancer-associated target. Due to the structural similarities of CAIX with other carbonic anhydrase isozymes, selective inhibition remains a significant challenge. A series of 3,4-substituted trifluorobenzenesulfonamides containing oxidized thiazine rings were synthesized using a novel synthetic pathway. Although the potency against CAIX was modestly reduced compared to more flexible analogs, selectivity increased significantly, with lead compounds 7 d and 7 e exhibiting over 1000-fold selectivity for CAIX over most other isozymes. X-ray crystallography revealed the structural basis for this selectivity, confirming the advantageous positioning of rigidified compounds within some CA isozyme active sites. These findings highlight the potential of molecular rigidity in the design of highly selective inhibitors for therapeutic applications.

Design of Rigid Compounds to Enhance Selectivity for Carbonic Anhydrase IX.,Vaskevicius A, Trumpickaite G, Parafjanovic E, Manakova E, Mickeviciute A, Gedgaudas M, Kojis T, Paketuryte-Latve V, Smirnov A, Baranauskiene L, Grazulis S, Zubriene A, Dudutiene V, Matulis D Chemistry. 2025 Mar 25;31(18):e202404409. doi: 10.1002/chem.202404409. Epub 2025 , Feb 17. PMID:39905940<ref>PMID:39905940</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9fn7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Manakova E]]
[[Category: Paketuryte V]]
[[Category: Smirnov A]]
[[Category: Trumpickaite G]]
[[Category: Vaskevicius A]]