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| ==yeast 20S proteasome in complex with the Syringolin-Glidobactin chimera== | | ==yeast 20S proteasome in complex with the Syringolin-Glidobactin chimera== |
- | <StructureSection load='4gk7' size='340' side='right' caption='[[4gk7]], [[Resolution|resolution]] 2.80Å' scene=''> | + | <StructureSection load='4gk7' size='340' side='right'caption='[[4gk7]], [[Resolution|resolution]] 2.80Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
- | <table><tr><td colspan='2'>[[4gk7]] is a 34 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GK7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GK7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gk7]] is a 24 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GK7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GK7 FirstGlance]. <br> |
- | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JT:(4R)-4-AMINO-5-METHYLHEXANOIC+ACID'>0JT</scene>, <scene name='pdbligand=LYH:3,4+ENE-LYSINE'>LYH</scene>, <scene name='pdbligand=MH9:(2E,4E)-DODECA-2,4-DIENOIC+ACID'>MH9</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]] 2.8Å</td></tr> |
- | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ryp|1ryp]], [[2zcy|2zcy]], [[3bdm|3bdm]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0JT:(4R)-4-AMINO-5-METHYLHEXANOIC+ACID'>0JT</scene>, <scene name='pdbligand=LYH:3,4+ENE-LYSINE'>LYH</scene>, <scene name='pdbligand=MH9:(2E,4E)-DODECA-2,4-DIENOIC+ACID'>MH9</scene></td></tr> |
- | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex Proteasome endopeptidase complex], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.25.1 3.4.25.1] </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=4gk7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gk7 OCA], [https://pdbe.org/4gk7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gk7 RCSB], [https://www.ebi.ac.uk/pdbsum/4gk7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gk7 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=4gk7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gk7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gk7 RCSB], [http://www.ebi.ac.uk/pdbsum/4gk7 PDBsum]</span></td></tr> | + | |
| </table> | | </table> |
- | <div style="background-color:#fffaf0;">
| + | == Function == |
- | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/PSA2_YEAST PSA2_YEAST] The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. It has an ATP-dependent proteolytic activity. |
- | Syrbactins belong to a recently emergent class of bacterial natural product inhibitors that irreversibly inhibit the proteasome of eukaryotes by a novel mechanism. The total syntheses of the syrbactin molecules syringolin A, syringolin B, and glidobactin A have been achieved, which allowed the preparation of syrbactin-inspired derivatives, such as the syringolin A-glidobactin A hybrid molecule (SylA-GlbA). To determine the potency of SylA-GlbA, we employed both in vitro and cell culture-based proteasome assays that measure the subcatalytic chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities. We further studied the inhibitory effects of SylA-GlbA on tumor cell growth using a panel of multiple myeloma, neuroblastoma, and ovarian cancer cell lines and showed that SylA-GlbA strongly blocks the activity of NF-kappaB. To gain more insights into the structure-activity relationship, we cocrystallized SylA-GlbA in complex with the proteasome and determined the X-ray structure. The electron density map displays covalent binding of the Thr1O(gamma) atoms of all active sites to the macrolactam ring of the ligand via ether bond formation, thus providing insights into the structure-activity relationship for the improved affinity of SylA-GlbA for the CT-L activity compared to those of the natural compounds SylA and GlbA. Our study revealed that the novel synthetic syrbactin compound represents one of the most potent proteasome inhibitors analyzed to date and therefore exhibits promising properties for improved drug development as an anticancer therapeutic.
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- | Activity Enhancement of the Synthetic Syrbactin Proteasome Inhibitor Hybrid and Biological Evaluation in Tumor Cells.,Archer CR, Groll M, Stein ML, Schellenberg B, Clerc J, Kaiser M, Kondratyuk TP, Pezzuto JM, Dudler R, Bachmann AS Biochemistry. 2012 Aug 17. PMID:22870914<ref>PMID:22870914</ref>
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- | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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- | </div>
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| ==See Also== | | ==See Also== |
- | *[[Proteasome|Proteasome]] | + | *[[Proteasome 3D structures|Proteasome 3D structures]] |
- | == References ==
| + | |
- | <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
- | [[Category: Proteasome endopeptidase complex]] | + | [[Category: Large Structures]] |
- | [[Category: Saccharomyces cerevisiae]] | + | [[Category: Saccharomyces cerevisiae S288C]] |
- | [[Category: Bachmann, A]] | + | [[Category: Synthetic construct]] |
- | [[Category: Groll, M]] | + | [[Category: Bachmann A]] |
- | [[Category: Stein, M L]] | + | [[Category: Groll M]] |
- | [[Category: 12-membered dipeptide-macrolactam]] | + | [[Category: Stein ML]] |
- | [[Category: Cancer]]
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- | [[Category: Hydrolase-hydrolase inhibitor complex]]
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- | [[Category: Inhibition]]
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- | [[Category: Natural product derivative]]
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- | [[Category: Ntn-hydrolase]]
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- | [[Category: Proteasome]]
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- | [[Category: Protein degradation]]
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