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| | <StructureSection load='6r6f' size='340' side='right'caption='[[6r6f]], [[Resolution|resolution]] 1.20Å' scene=''> | | <StructureSection load='6r6f' size='340' side='right'caption='[[6r6f]], [[Resolution|resolution]] 1.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6r6f]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R6F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R6F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6r6f]] 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=6R6F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R6F FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EA3:4-chloranyl-2-cyclohexylsulfanyl-~{N}-(2-hydroxyethyl)-5-sulfamoyl-benzamide'>EA3</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"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EA3:4-chloranyl-2-cyclohexylsulfanyl-~{N}-(2-hydroxyethyl)-5-sulfamoyl-benzamide'>EA3</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='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='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=6r6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6f OCA], [http://pdbe.org/6r6f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r6f RCSB], [http://www.ebi.ac.uk/pdbsum/6r6f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6f ProSAT]</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=6r6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6f OCA], [http://pdbe.org/6r6f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r6f RCSB], [http://www.ebi.ac.uk/pdbsum/6r6f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6f ProSAT]</span></td></tr> |
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| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | The endosomal Toll-like receptor 8 (TLR8) recognizes single-stranded RNA and initiates early inflammatory responses. Despite the importance of endosomal TLRs for human host defense against microbial pathogens, extensive activation may contribute to autoimmune and inflammatory diseases. In contrast to the recent progress made in the development of modulators of plasma membrane-bound TLRs, little is known about endosomal TLR modulation and very few TLR8 inhibitors have been reported. In this study, we discovered and validated novel small-molecule TLR8 inhibitors. Fourteen potential TLR8 modulators were experimentally validated in HEK293T cells stably overexpressing human TLR8 and THP-1 macrophages. Five compounds inhibited TLR8-mediated signaling, representing a hit rate of 36%. The three most potent compounds neither cause cellular toxicity nor inhibition of TLR signaling induced by other receptor subtypes. Conclusively, we experimentally confirm novel and selective, pyrimidine-based TLR8 inhibitors with low cytotoxicity that are relevant candidates for lead optimization and further mechanistic studies.
| + | By applying an approach of a "ring with two tails", a series of novel inhibitors possessing high-affinity and significant selectivity towards selected carbonic anhydrase (CA) isoforms has been designed. The "ring" consists of 2-chloro/bromo-benzenesulfonamide, where the sulfonamide group is as an anchor coordinating the Zn(II) in the active site of CAs, and halogen atom orients the ring affecting the affinity and selectivity. First "tail" is a substituent containing carbonyl, carboxyl, hydroxyl, ether groups or hydrophilic amide linkage. The second "tail" contains aryl- or alkyl-substituents attached through a sulfanyl or sulfonyl group. Both "tails" are connected to the benzene ring and play a crucial role in selectivity. Varying the substituents, we designed compounds selective for CA VII, CA IX, CA XII, or CA XIV. Since due to binding-linked protonation reactions the binding-ready fractions of the compound and protein are much lower than one, the "intrinsic" affinities were calculated that should be used to study correlations between crystal structures and the thermodynamics of binding for rational drug design. The "intrinsic" affinities together with the intrinsic enthalpies and entropies of binding together with co-crystal structures were used demonstrate structural factors determining major contributions for compound affinity and selectivity. |
| | | | |
| - | Identification and characterization of a novel chemotype for human TLR8 inhibitors.,Sribar D, Grabowski M, Murgueitio MS, Bermudez M, Weindl G, Wolber G Eur J Med Chem. 2019 Oct 1;179:744-752. doi: 10.1016/j.ejmech.2019.06.084. Epub, 2019 Jun 29. PMID:31284084<ref>PMID:31284084</ref>
| + | Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms.,Zaksauskas A, Capkauskaite E, Jezepcikas L, Linkuviene V, Paketuryte V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Manakova E, Grazulis S, Tars K, Matulis D Eur J Med Chem. 2020 Jan 1;185:111825. doi: 10.1016/j.ejmech.2019.111825. Epub, 2019 Oct 31. PMID:31740053<ref>PMID:31740053</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Carbonate dehydratase]] | | [[Category: Carbonate dehydratase]] |
| | + | [[Category: Human]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| | [[Category: Grazulis, S]] | | [[Category: Grazulis, S]] |
| Structural highlights
Disease
[CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM: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.[1] [2] [3] [4] [5]
Function
[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.[6] [7]
Publication Abstract from PubMed
By applying an approach of a "ring with two tails", a series of novel inhibitors possessing high-affinity and significant selectivity towards selected carbonic anhydrase (CA) isoforms has been designed. The "ring" consists of 2-chloro/bromo-benzenesulfonamide, where the sulfonamide group is as an anchor coordinating the Zn(II) in the active site of CAs, and halogen atom orients the ring affecting the affinity and selectivity. First "tail" is a substituent containing carbonyl, carboxyl, hydroxyl, ether groups or hydrophilic amide linkage. The second "tail" contains aryl- or alkyl-substituents attached through a sulfanyl or sulfonyl group. Both "tails" are connected to the benzene ring and play a crucial role in selectivity. Varying the substituents, we designed compounds selective for CA VII, CA IX, CA XII, or CA XIV. Since due to binding-linked protonation reactions the binding-ready fractions of the compound and protein are much lower than one, the "intrinsic" affinities were calculated that should be used to study correlations between crystal structures and the thermodynamics of binding for rational drug design. The "intrinsic" affinities together with the intrinsic enthalpies and entropies of binding together with co-crystal structures were used demonstrate structural factors determining major contributions for compound affinity and selectivity.
Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms.,Zaksauskas A, Capkauskaite E, Jezepcikas L, Linkuviene V, Paketuryte V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Manakova E, Grazulis S, Tars K, Matulis D Eur J Med Chem. 2020 Jan 1;185:111825. doi: 10.1016/j.ejmech.2019.111825. Epub, 2019 Oct 31. PMID:31740053[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Venta PJ, Welty RJ, Johnson TM, Sly WS, Tashian RE. Carbonic anhydrase II deficiency syndrome in a Belgian family is caused by a point mutation at an invariant histidine residue (107 His----Tyr): complete structure of the normal human CA II gene. Am J Hum Genet. 1991 Nov;49(5):1082-90. PMID:1928091
- ↑ Roth DE, Venta PJ, Tashian RE, Sly WS. Molecular basis of human carbonic anhydrase II deficiency. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1804-8. PMID:1542674
- ↑ Soda H, Yukizane S, Yoshida I, Koga Y, Aramaki S, Kato H. A point mutation in exon 3 (His 107-->Tyr) in two unrelated Japanese patients with carbonic anhydrase II deficiency with central nervous system involvement. Hum Genet. 1996 Apr;97(4):435-7. PMID:8834238
- ↑ Hu PY, Lim EJ, Ciccolella J, Strisciuglio P, Sly WS. Seven novel mutations in carbonic anhydrase II deficiency syndrome identified by SSCP and direct sequencing analysis. Hum Mutat. 1997;9(5):383-7. PMID:9143915 doi:<383::AID-HUMU1>3.0.CO;2-5 10.1002/(SICI)1098-1004(1997)9:5<383::AID-HUMU1>3.0.CO;2-5
- ↑ Shah GN, Bonapace G, Hu PY, Strisciuglio P, Sly WS. Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation. Hum Mutat. 2004 Sep;24(3):272. PMID:15300855 doi:10.1002/humu.9266
- ↑ Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT. Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? J Biol Inorg Chem. 1999 Oct;4(5):528-36. PMID:10550681
- ↑ Kim CY, Whittington DA, Chang JS, Liao J, May JA, Christianson DW. Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. J Med Chem. 2002 Feb 14;45(4):888-93. PMID:11831900
- ↑ Zaksauskas A, Capkauskaite E, Jezepcikas L, Linkuviene V, Paketuryte V, Smirnov A, Leitans J, Kazaks A, Dvinskis E, Manakova E, Grazulis S, Tars K, Matulis D. Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms. Eur J Med Chem. 2020 Jan 1;185:111825. doi: 10.1016/j.ejmech.2019.111825. Epub, 2019 Oct 31. PMID:31740053 doi:http://dx.doi.org/10.1016/j.ejmech.2019.111825
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