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7puu

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Current revision

Crystal structure of carbonic anhydrase XII with methyl 4-chloro-2-cyclohexylsulfanyl-5-sulfamoylbenzoate

Structural highlights

7puu is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.51Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX.,Zaksauskas A, Capkauskaite E, Paketuryte-Latve V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Stancaitis L, Mickeviciute A, Jachno J, Jezepcikas L, Linkuviene V, Sakalauskas A, Manakova E, Grazulis S, Matuliene J, Tars K, Matulis D Int J Mol Sci. 2021 Dec 23;23(1). pii: ijms23010130. doi: 10.3390/ijms23010130. PMID:35008553^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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, Paketuryte-Latve V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Stancaitis L, Mickeviciute A, Jachno J, Jezepcikas L, Linkuviene V, Sakalauskas A, Manakova E, Grazulis S, Matuliene J, Tars K, Matulis D. Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX. Int J Mol Sci. 2021 Dec 23;23(1). pii: ijms23010130. doi: 10.3390/ijms23010130. PMID:35008553 doi:http://dx.doi.org/10.3390/ijms23010130

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7puu"

Categories: Homo sapiens | Large Structures | Grazulis S | Manakova E | Smirnov A

@@ Line 3: / Line 3: @@
 <StructureSection load='7puu' size='340' side='right'caption='[[7puu]], [[Resolution|resolution]] 1.51&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7puu]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PUU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PUU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7puu]] 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=7PUU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PUU FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=84O:methyl+4-chloranyl-2-cyclohexylsulfanyl-5-sulfamoyl-benzoate'>84O</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.51&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=84O:methyl+4-chloranyl-2-cyclohexylsulfanyl-5-sulfamoyl-benzoate'>84O</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=7puu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7puu OCA], [https://pdbe.org/7puu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7puu RCSB], [https://www.ebi.ac.uk/pdbsum/7puu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7puu 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>
+[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.
+[https://www.uniprot.org/uniprot/CAH12_HUMAN CAH12_HUMAN] Reversible hydration of carbon dioxide.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 21: @@
 </div>
 <div class="pdbe-citations 7puu" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Carbonate dehydratase]]
+[[Category: Homo sapiens]]
 [[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]]

7puu

From Proteopedia

Current revision

Crystal structure of carbonic anhydrase XII with methyl 4-chloro-2-cyclohexylsulfanyl-5-sulfamoylbenzoate

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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