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''' | ==Crystal structure of human carbonic anhydrase isozyme I with 2,3,5,6-Tetrafluoro-4-piperidin-1-ylbenzenesulfonamide== | ||
<StructureSection load='4wuq' size='340' side='right' caption='[[4wuq]], [[Resolution|resolution]] 1.75Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4wuq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WUQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WUQ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3UG:2,3,5,6-TETRAFLUORO-4-(PIPERIDIN-1-YL)BENZENESULFONAMIDE'>3UG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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">[[4wr7|4wr7]], [[4wup|4wup]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wuq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wuq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4wuq RCSB], [http://www.ebi.ac.uk/pdbsum/4wuq PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/CAH1_HUMAN CAH1_HUMAN]] Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.<ref>PMID:10550681</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Para substituted tetrafluorobenzenesulfonamides bind to carbonic anhydrases (CAs) extremely tightly and exhibit some of the strongest known protein-small ligand interactions, reaching an intrinsic affinity of 2 pM as determined by displacement isothermal titration calorimetry (ITC). The enthalpy and entropy of binding to five CA isoforms were measured by ITC in two buffers of different protonation enthalpies. The pKa values of compound sulfonamide groups were measured potentiometrically and spectrophotometrically, and enthalpies of protonation were measured by ITC in order to evaluate the proton linkage contributions to the observed binding thermodynamics. Intrinsic means the affinity of a sulfonamide anion for the Zn bound water form of CAs. Fluorination of the benzene ring significantly enhanced the observed affinities as it increased the fraction of deprotonated ligand while having little impact on intrinsic affinities. Intrinsic enthalpy contributions to the binding affinity were dominant over entropy and were more exothermic for CA I than for other CA isoforms. Thermodynamic measurements together with the X-ray crystallographic structures of protein-ligand complexes enabled analysis of structure-activity relationships in this enzyme ligand system. | |||
Intrinsic thermodynamics of 4-substituted-2,3,5,6-tetrafluorobenzenesulfonamide binding to carbonic anhydrases by isothermal titration calorimetry.,Zubriene A, Smirnoviene J, Smirnov A, Morkunaite V, Michailoviene V, Jachno J, Juozapaitiene V, Norvaisas P, Manakova E, Grazulis S, Matulis D Biophys Chem. 2015 Jun 6;205:51-65. doi: 10.1016/j.bpc.2015.05.009. PMID:26079542<ref>PMID:26079542</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Carbonate dehydratase]] | |||
[[Category: Grazulis, S]] | [[Category: Grazulis, S]] | ||
[[Category: Manakova, E]] | |||
[[Category: Smirnov, A]] | [[Category: Smirnov, A]] | ||
[[Category: | [[Category: Benzenesulfonamide]] | ||
[[Category: Carbonic anhydrase]] | |||
[[Category: Drug design]] | |||
[[Category: Lyase]] | |||
[[Category: Lyase-lyase inhibitor complex]] | |||
[[Category: Metal-binding]] | |||
Revision as of 15:04, 1 July 2015
Crystal structure of human carbonic anhydrase isozyme I with 2,3,5,6-Tetrafluoro-4-piperidin-1-ylbenzenesulfonamideCrystal structure of human carbonic anhydrase isozyme I with 2,3,5,6-Tetrafluoro-4-piperidin-1-ylbenzenesulfonamide
Structural highlights
Function[CAH1_HUMAN] Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.[1] Publication Abstract from PubMedPara substituted tetrafluorobenzenesulfonamides bind to carbonic anhydrases (CAs) extremely tightly and exhibit some of the strongest known protein-small ligand interactions, reaching an intrinsic affinity of 2 pM as determined by displacement isothermal titration calorimetry (ITC). The enthalpy and entropy of binding to five CA isoforms were measured by ITC in two buffers of different protonation enthalpies. The pKa values of compound sulfonamide groups were measured potentiometrically and spectrophotometrically, and enthalpies of protonation were measured by ITC in order to evaluate the proton linkage contributions to the observed binding thermodynamics. Intrinsic means the affinity of a sulfonamide anion for the Zn bound water form of CAs. Fluorination of the benzene ring significantly enhanced the observed affinities as it increased the fraction of deprotonated ligand while having little impact on intrinsic affinities. Intrinsic enthalpy contributions to the binding affinity were dominant over entropy and were more exothermic for CA I than for other CA isoforms. Thermodynamic measurements together with the X-ray crystallographic structures of protein-ligand complexes enabled analysis of structure-activity relationships in this enzyme ligand system. Intrinsic thermodynamics of 4-substituted-2,3,5,6-tetrafluorobenzenesulfonamide binding to carbonic anhydrases by isothermal titration calorimetry.,Zubriene A, Smirnoviene J, Smirnov A, Morkunaite V, Michailoviene V, Jachno J, Juozapaitiene V, Norvaisas P, Manakova E, Grazulis S, Matulis D Biophys Chem. 2015 Jun 6;205:51-65. doi: 10.1016/j.bpc.2015.05.009. PMID:26079542[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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