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| | ==Crystal structure of Eosinophil-derived neurotoxin in complex with the triazole double-headed ribonucleoside 11c== | | ==Crystal structure of Eosinophil-derived neurotoxin in complex with the triazole double-headed ribonucleoside 11c== |
| - | <StructureSection load='5e13' size='340' side='right' caption='[[5e13]], [[Resolution|resolution]] 1.34Å' scene=''> | + | <StructureSection load='5e13' size='340' side='right'caption='[[5e13]], [[Resolution|resolution]] 1.34Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e13]] 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=5E13 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5E13 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e13]] 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=5E13 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E13 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5J9:3-{4-[(4-AMINO-2-OXOPYRIMIDIN-1(2H)-YL)METHYL]-1H-1,2,3-TRIAZOL-1-YL}-3-DEOXYADENOSINE'>5J9</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]] 1.34Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RNASE2, EDN, RNS2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5J9:3-{4-[(4-AMINO-2-OXOPYRIMIDIN-1(2H)-YL)METHYL]-1H-1,2,3-TRIAZOL-1-YL}-3-DEOXYADENOSINE'>5J9</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pancreatic_ribonuclease Pancreatic ribonuclease], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.27.5 3.1.27.5] </span></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=5e13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e13 OCA], [https://pdbe.org/5e13 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e13 RCSB], [https://www.ebi.ac.uk/pdbsum/5e13 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e13 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=5e13 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e13 OCA], [http://pdbe.org/5e13 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e13 RCSB], [http://www.ebi.ac.uk/pdbsum/5e13 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e13 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RNAS2_HUMAN RNAS2_HUMAN]] This is a non-secretory ribonuclease. It is a pyrimidine specific nuclease with a slight preference for U. Cytotoxin and helminthotoxin. Selectively chemotactic for dendritic cells. Possesses a wide variety of biological activities.<ref>PMID:3458170</ref> <ref>PMID:12578357</ref> | + | [https://www.uniprot.org/uniprot/RNAS2_HUMAN RNAS2_HUMAN] This is a non-secretory ribonuclease. It is a pyrimidine specific nuclease with a slight preference for U. Cytotoxin and helminthotoxin. Selectively chemotactic for dendritic cells. Possesses a wide variety of biological activities.<ref>PMID:3458170</ref> <ref>PMID:12578357</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Pancreatic ribonuclease]] | + | [[Category: Large Structures]] |
| - | [[Category: Chatzileontiadou, D S.M]] | + | [[Category: Chatzileontiadou DSM]] |
| - | [[Category: Kantsadi, A L]] | + | [[Category: Kantsadi AL]] |
| - | [[Category: Leonidas, D D]] | + | [[Category: Leonidas DD]] |
| - | [[Category: Stravodimos, G A]] | + | [[Category: Stravodimos GA]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Nuclease]]
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| Structural highlights
Function
RNAS2_HUMAN This is a non-secretory ribonuclease. It is a pyrimidine specific nuclease with a slight preference for U. Cytotoxin and helminthotoxin. Selectively chemotactic for dendritic cells. Possesses a wide variety of biological activities.[1] [2]
Publication Abstract from PubMed
Eosinophil derived neurotoxin (EDN) is an eosinophil secretion protein and a member of the Ribonuclease A (RNase A) superfamily involved in the immune response system and inflammatory disorders. The pathological actions of EDN are strongly dependent on the enzymatic activity and therefore, it is of significant interest to discover potent and specific inhibitors of EDN. In this framework we have assessed the inhibitory potency of triazole double-headed ribonucleosides. We present here an efficient method for the heterologous production and purification of EDN together with the synthesis of nucleosides and their biochemical evaluation in RNase A and EDN. Two groups of double-headed nucleosides were synthesized by the attachment of a purine or a pyrimidine base, through a triazole group at the 3'-C position of a pyrimidine or a purine ribonucleoside, respectively. Based on previous data with mononucleosides these compounds were expected to improve the inhibitory potency for RNase A and specificity for EDN. Kinetics data revealed that despite the rational, all but one, double-headed ribonucleosides were less potent than the respective mononucleosides while they were also more specific for ribonuclease A than for EDN. Compound 11c (9-[3'-[4-[(cytosine-1-yl)methyl]-1,2,3-triazol-1-yl]-beta-d-ribofuranosyl]adenin e) displayed a stronger preference for EDN than for ribonuclease A and a Ki value of 58muM. This is the first time that an inhibitor is reported to have a better potency for EDN than for RNase A. The crystal structure of EDN-11c complex reveals the structural basis of its potency and selectivity providing important guidelines for future structure-based inhibitor design efforts.
Triazole double-headed ribonucleosides as inhibitors of eosinophil derived neurotoxin.,Chatzileontiadou DS, Parmenopoulou V, Manta S, Kantsadi AL, Kylindri P, Griniezaki M, Kontopoulou F, Telopoulou A, Prokova H, Panagopoulos D, Boix E, Balatsos NA, Komiotis D, Leonidas DD Bioorg Chem. 2015 Dec;63:152-65. doi: 10.1016/j.bioorg.2015.10.007. Epub 2015 Oct, 31. PMID:26551065[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gleich GJ, Loegering DA, Bell MP, Checkel JL, Ackerman SJ, McKean DJ. Biochemical and functional similarities between human eosinophil-derived neurotoxin and eosinophil cationic protein: homology with ribonuclease. Proc Natl Acad Sci U S A. 1986 May;83(10):3146-50. PMID:3458170
- ↑ Teufel DP, Kao RY, Acharya KR, Shapiro R. Mutational analysis of the complex of human RNase inhibitor and human eosinophil-derived neurotoxin (RNase 2). Biochemistry. 2003 Feb 18;42(6):1451-9. PMID:12578357 doi:10.1021/bi026852o
- ↑ Chatzileontiadou DS, Parmenopoulou V, Manta S, Kantsadi AL, Kylindri P, Griniezaki M, Kontopoulou F, Telopoulou A, Prokova H, Panagopoulos D, Boix E, Balatsos NA, Komiotis D, Leonidas DD. Triazole double-headed ribonucleosides as inhibitors of eosinophil derived neurotoxin. Bioorg Chem. 2015 Dec;63:152-65. doi: 10.1016/j.bioorg.2015.10.007. Epub 2015 Oct, 31. PMID:26551065 doi:http://dx.doi.org/10.1016/j.bioorg.2015.10.007
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