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| ==Human carbonic anhydrase II in complex with tert-butyl 4-(4-sulfamoylphenoxy)butylcarbamate== | | ==Human carbonic anhydrase II in complex with tert-butyl 4-(4-sulfamoylphenoxy)butylcarbamate== |
| <StructureSection load='4rfc' size='340' side='right' caption='[[4rfc]], [[Resolution|resolution]] 1.65Å' scene=''> | | <StructureSection load='4rfc' size='340' side='right'caption='[[4rfc]], [[Resolution|resolution]] 1.65Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4rfc]] is a 1 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=4RFC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RFC FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4rfc]] is a 1 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=4RFC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RFC FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3O1:TERT-BUTYL+4-(4-SULFAMOYLPHENOXY)BUTYLCARBAMATE'>3O1</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]] 1.645Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rfd|4rfd]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3O1:TERT-BUTYL+4-(4-SULFAMOYLPHENOXY)BUTYLCARBAMATE'>3O1</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4rfc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfc OCA], [https://pdbe.org/4rfc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rfc RCSB], [https://www.ebi.ac.uk/pdbsum/4rfc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfc ProSAT]</span></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>
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| <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=4rfc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfc OCA], [http://pdbe.org/4rfc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rfc RCSB], [http://www.ebi.ac.uk/pdbsum/4rfc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfc ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Disease == | | == Disease == |
| [[http://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN]] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:[http://omim.org/entry/259730 259730]]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.<ref>PMID:1928091</ref> <ref>PMID:1542674</ref> <ref>PMID:8834238</ref> <ref>PMID:9143915</ref> <ref>PMID:15300855</ref> | | [https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:[https://omim.org/entry/259730 259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.<ref>PMID:1928091</ref> <ref>PMID:1542674</ref> <ref>PMID:8834238</ref> <ref>PMID:9143915</ref> <ref>PMID:15300855</ref> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN]] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.<ref>PMID:10550681</ref> <ref>PMID:11831900</ref> | | [https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.<ref>PMID:10550681</ref> <ref>PMID:11831900</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| We report a series of 4-sulfamoylphenyl-omega-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII.
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| A class of 4-sulfamoylphenyl-omega-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects.,Bozdag M, Pinard M, Carta F, Masini E, Scozzafava A, McKenna R, Supuran CT J Med Chem. 2014 Nov 26;57(22):9673-86. doi: 10.1021/jm501497m. Epub 2014 Nov 10. PMID:25358036<ref>PMID:25358036</ref>
| | ==See Also== |
| | | *[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 4rfc" style="background-color:#fffaf0;"></div>
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| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Carbonate dehydratase]] | | [[Category: Homo sapiens]] |
| [[Category: Human]] | | [[Category: Large Structures]] |
| [[Category: Bozdag, M]] | | [[Category: Bozdag M]] |
| [[Category: Carta, F]] | | [[Category: Carta F]] |
| [[Category: Masini, E]] | | [[Category: Masini E]] |
| [[Category: Mckenna, R]] | | [[Category: Mckenna R]] |
| [[Category: Pinard, M A]] | | [[Category: Pinard MA]] |
| [[Category: Scozzafava, A]] | | [[Category: Scozzafava A]] |
| [[Category: Supuran, C T]] | | [[Category: Supuran CT]] |
| [[Category: Antiglaucoma]]
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| [[Category: Carbonic anhydrase]]
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| [[Category: Lyase]]
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| [[Category: Sulfonamide]]
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