4q0l

From Proteopedia

(Difference between revisions)

Revision as of 07:39, 8 February 2023

Crystal structure of catalytic domain of human carbonic anhydrase isozyme XII with inhibitor

Structural highlights

4q0l 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.
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

Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound's co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX's catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.

Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.,Dudutiene V, Matuliene J, Smirnov A, Timm DD, Zubriene A, Baranauskiene L, Morkunaite V, Smirnoviene J, Michailoviene V, Juozapaitiene V, Mickeviciute A, Kazokaite J, Baksyte S, Kasiliauskaite A, Jachno J, Revuckiene J, Kisonaite M, Pilipuityte V, Ivanauskaite E, Milinaviciute G, Smirnovas V, Petrikaite V, Kairys V, Petrauskas V, Norvaisas P, Linge D, Gibieza P, Capkauskaite E, Zaksauskas A, Kazlauskas E, Manakova E, Grazulis S, Ladbury JE, Matulis D J Med Chem. 2014 Nov 26;57(22):9435-46. doi: 10.1021/jm501003k. Epub 2014 Nov 10. PMID:25358084^[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
↑ Dudutiene V, Matuliene J, Smirnov A, Timm DD, Zubriene A, Baranauskiene L, Morkunaite V, Smirnoviene J, Michailoviene V, Juozapaitiene V, Mickeviciute A, Kazokaite J, Baksyte S, Kasiliauskaite A, Jachno J, Revuckiene J, Kisonaite M, Pilipuityte V, Ivanauskaite E, Milinaviciute G, Smirnovas V, Petrikaite V, Kairys V, Petrauskas V, Norvaisas P, Linge D, Gibieza P, Capkauskaite E, Zaksauskas A, Kazlauskas E, Manakova E, Grazulis S, Ladbury JE, Matulis D. Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX. J Med Chem. 2014 Nov 26;57(22):9435-46. doi: 10.1021/jm501003k. Epub 2014 Nov 10. PMID:25358084 doi:http://dx.doi.org/10.1021/jm501003k

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/4q0l"

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

@@ Line 1: / Line 1: @@
 ==Crystal structure of catalytic domain of human carbonic anhydrase isozyme XII with inhibitor==
-<StructureSection load='4q0l' size='340' side='right' caption='[[4q0l]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='4q0l' size='340' side='right'caption='[[4q0l]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4q0l]] 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=4Q0L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q0L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4q0l]] 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=4Q0L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q0L FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=V14:3-(CYCLOOCTYLAMINO)-2,5,6-TRIFLUORO-4-[(2-HYDROXYETHYL)SULFONYL]BENZENESULFONAMIDE'>V14</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V14:3-(CYCLOOCTYLAMINO)-2,5,6-TRIFLUORO-4-[(2-HYDROXYETHYL)SULFONYL]BENZENESULFONAMIDE'>V14</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">[[4pyx|4pyx]], [[4pyy|4pyy]], [[4pzh|4pzh]], [[4q06|4q06]], [[4q07|4q07]], [[4q08|4q08]], [[4q09|4q09]]</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=4q0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q0l OCA], [https://pdbe.org/4q0l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q0l RCSB], [https://www.ebi.ac.uk/pdbsum/4q0l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q0l ProSAT]</span></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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4q0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q0l OCA], [http://pdbe.org/4q0l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4q0l RCSB], [http://www.ebi.ac.uk/pdbsum/4q0l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4q0l ProSAT]</span></td></tr>
 </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>
+[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 ==
-[[http://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 23: / Line 20: @@
 </div>
 <div class="pdbe-citations 4q0l" 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: Human]]
+[[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-lyase inhibitor comple]]
-[[Category: Lyase-lyase inhibitor complex]]
-[[Category: Metal-binding]]

4q0l

From Proteopedia

Revision as of 07:39, 8 February 2023

Crystal structure of catalytic domain of human carbonic anhydrase isozyme XII with inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox