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| | ==Structure of Chlamydia trachomatis effector protein Cdu1 bound to ubiquitin== | | ==Structure of Chlamydia trachomatis effector protein Cdu1 bound to ubiquitin== |
| - | <StructureSection load='6fdk' size='340' side='right' caption='[[6fdk]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='6fdk' size='340' side='right'caption='[[6fdk]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6fdk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Chlt2 Chlt2] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FDK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FDK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6fdk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Chlamydia_trachomatis_434/Bu Chlamydia trachomatis 434/Bu] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FDK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FDK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AYE:PROP-2-EN-1-AMINE'>AYE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AYE:PROP-2-EN-1-AMINE'>AYE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5b5q|5b5q]], [[5hag|5hag]]</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=6fdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fdk OCA], [https://pdbe.org/6fdk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fdk RCSB], [https://www.ebi.ac.uk/pdbsum/6fdk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fdk ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cdu1, CTL0247 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=471472 CHLT2]), UBB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6fdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fdk OCA], [http://pdbe.org/6fdk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fdk RCSB], [http://www.ebi.ac.uk/pdbsum/6fdk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fdk ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CDUB1_CHLT2 CDUB1_CHLT2]] Effector proteins function to alter host cell physiology and promote bacterial survival in host tissues. This protease possesses deubiquitinating and deneddylating activities (By similarity). Impairs ubiquitination and degradation of NF-kappa-B inhibitor alpha (NFKBIA), thereby preventing NF-kappa-B activation.<ref>PMID:18503636</ref> [[http://www.uniprot.org/uniprot/UBB_HUMAN UBB_HUMAN]] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref> | + | [https://www.uniprot.org/uniprot/CDUB1_CHLT2 CDUB1_CHLT2] Effector proteins function to alter host cell physiology and promote bacterial survival in host tissues. This protease possesses deubiquitinating and deneddylating activities (By similarity). Impairs ubiquitination and degradation of NF-kappa-B inhibitor alpha (NFKBIA), thereby preventing NF-kappa-B activation.<ref>PMID:18503636</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Ubiquitin|Ubiquitin]] | + | *[[3D structures of ubiquitin|3D structures of ubiquitin]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chlt2]] | + | [[Category: Chlamydia trachomatis 434/Bu]] |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kisker, C]] | + | [[Category: Large Structures]] |
| - | [[Category: Ramirez, Y]] | + | [[Category: Kisker C]] |
| - | [[Category: Ce protease]] | + | [[Category: Ramirez Y]] |
| - | [[Category: Chladub1]]
| + | |
| - | [[Category: Dub]]
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| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Ubiquitin]]
| + | |
| Structural highlights
Function
CDUB1_CHLT2 Effector proteins function to alter host cell physiology and promote bacterial survival in host tissues. This protease possesses deubiquitinating and deneddylating activities (By similarity). Impairs ubiquitination and degradation of NF-kappa-B inhibitor alpha (NFKBIA), thereby preventing NF-kappa-B activation.[1]
Publication Abstract from PubMed
Based on the similarity between the active sites of the deubiquitylating and deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionary related protease adenain a target-hopping approach screening on a focused set of adenain inhibitors has been pursued. The thereby identified cyano-pyrimidine based inhibitors represent the first active-site directed small molecule inhibitors for Cdu1. High-resolution crystal structures of Cdu1 in complex with two covalently bound cyano-pyrimidines as well as with its substrate ubiquitin have been obtained. These structural data were complemented by enzymatic assays and covalent docking studies to provide insight into Cdu1s substrate recognition, active site pocket flexibility and potential hotspots for ligand interaction. Combined, these data provide a strong foundation for future structure-guided medicinal chemistry optimization of this cyano-pyrimidine based scaffold towards more potent and specific Cdu1 inhibitors.
Structural basis of substrate recognition and covalent inhibition of Cdu1 from Chlamydia trachomatis.,Ramirez YA, Adler T, Altmann E, Tiesmeyer C, Klemm T, Sauer F, Kathman S, Statsyuk A, Sotriffer C, Kisker C ChemMedChem. 2018 Jul 20. doi: 10.1002/cmdc.201800364. PMID:30028574[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Le Negrate G, Krieg A, Faustin B, Loeffler M, Godzik A, Krajewski S, Reed JC. ChlaDub1 of Chlamydia trachomatis suppresses NF-kappaB activation and inhibits IkappaBalpha ubiquitination and degradation. Cell Microbiol. 2008 Sep;10(9):1879-92. doi: 10.1111/j.1462-5822.2008.01178.x., Epub 2008 Jun 28. PMID:18503636 doi:http://dx.doi.org/10.1111/j.1462-5822.2008.01178.x
- ↑ Ramirez YA, Adler T, Altmann E, Tiesmeyer C, Klemm T, Sauer F, Kathman S, Statsyuk A, Sotriffer C, Kisker C. Structural basis of substrate recognition and covalent inhibition of Cdu1 from Chlamydia trachomatis. ChemMedChem. 2018 Jul 20. doi: 10.1002/cmdc.201800364. PMID:30028574 doi:http://dx.doi.org/10.1002/cmdc.201800364
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