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| - | {{Large structure}} | |
| - | {{STRUCTURE_4jsq| PDB=4jsq | SCENE= }} | |
| - | ===Yeast 20S proteasome in complex with the dimerized linear mimetic of TMC-95A - yCP:4e=== | |
| - | {{ABSTRACT_PUBMED_23540790}} | |
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| - | ==Function== | + | ==Yeast 20S proteasome in complex with the dimerized linear mimetic of TMC-95A - yCP:4e== |
| - | [[http://www.uniprot.org/uniprot/PSA7_YEAST PSA7_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. [[http://www.uniprot.org/uniprot/PSB5_YEAST PSB5_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. This unit is responsible of the chymotrypsin-like activity of the proteasome and is one of the principal target of the proteasome inhibitor bortezomib. This subunit is necessary for chymotryptic activity and degradation of ubiquitinated proteins. [[http://www.uniprot.org/uniprot/PSA4_YEAST PSA4_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. [[http://www.uniprot.org/uniprot/PSA1_YEAST PSA1_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. [[http://www.uniprot.org/uniprot/PSB3_YEAST PSB3_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. This subunit may participate in the trypsin-like activity of the enzyme complex. [[http://www.uniprot.org/uniprot/PSA3_YEAST PSA3_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. [[http://www.uniprot.org/uniprot/PSB6_YEAST PSB6_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. [[http://www.uniprot.org/uniprot/PSB1_YEAST PSB1_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. PRE3 and PRE4 are necessary for the peptidyl-glutamyl-peptide-hydrolyzing activity. This subunit is necessary for the peptidylglutamyl-peptide hydrolyzing activity. [[http://www.uniprot.org/uniprot/PSB2_YEAST PSB2_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. [[http://www.uniprot.org/uniprot/PSA5_YEAST PSA5_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. [[http://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. [[http://www.uniprot.org/uniprot/PSB4_YEAST PSB4_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. This subunit has a chymotrypsin-like activity. [[http://www.uniprot.org/uniprot/PSB7_YEAST PSB7_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. PRE3 and PRE4 are necessary for the peptidyl-glutamyl-peptide-hydrolyzing activity.<ref>PMID:8381431</ref> [[http://www.uniprot.org/uniprot/PSA6_YEAST PSA6_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. | + | <StructureSection load='4jsq' size='340' side='right'caption='[[4jsq]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[4jsq]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JSQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JSQ FirstGlance]. <br> |
| | + | </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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ABN:BENZYLAMINE'>ABN</scene>, <scene name='pdbligand=ACA:6-AMINOHEXANOIC+ACID'>ACA</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=RE0:3-[(3R)-3-HYDROXY-2-OXO-2,3-DIHYDRO-1H-INDOL-3-YL]-L-ALANINE'>RE0</scene>, <scene name='pdbligand=TY5:O-BENZYL-L-TYROSINE'>TY5</scene></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=4jsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsq OCA], [https://pdbe.org/4jsq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jsq RCSB], [https://www.ebi.ac.uk/pdbsum/4jsq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jsq ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PSB1_YEAST PSB1_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. PRE3 and PRE4 are necessary for the peptidyl-glutamyl-peptide-hydrolyzing activity. This subunit is necessary for the peptidylglutamyl-peptide hydrolyzing activity. |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously two of the six active sites of the eukaryotic 20S proteasome. The homodimerized compounds actively inhibited chymotrypsin-like (Ki = 6-11 nM) and trypsin-like activities, whereas postacid activity was poorly modified. The noncovalent binding mode was ascertained by X-ray crystallography of the inhibitors complexed with the yeast 20S proteasome. The inhibition of proteasomal activities in human cells was evaluated. The use of the multivalency inhibitor concept has produced highly efficient and selective noncovalent compounds (no inhibition of calpain and cathepsin) that have potential therapeutic advantages compared to covalent binders such as bortezomib and carfilzomib. |
| | | | |
| - | ==About this Structure==
| + | Dimerized Linear Mimics of a Natural Cyclopeptide (TMC-95A) Are Potent Noncovalent Inhibitors of the Eukaryotic 20S Proteasome.,Desvergne A, Genin E, Marechal X, Gallastegui N, Dufau L, Richy N, Groll M, Vidal J, Reboud-Ravaux M J Med Chem. 2013 Apr 25;56(8):3367-78. doi: 10.1021/jm4002007. Epub 2013 Apr 17. PMID:23540790<ref>PMID:23540790</ref> |
| - | [[4jsq]] is a 30 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=4JSQ OCA].
| + | |
| | | | |
| - | ==See Also== | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | *[[Proteasome|Proteasome]]
| + | </div> |
| | + | <div class="pdbe-citations 4jsq" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | <ref group="xtra">PMID:023540790</ref><references group="xtra"/><references/>
| + | *[[Proteasome 3D structures|Proteasome 3D structures]] |
| - | [[Category: Proteasome endopeptidase complex]] | + | == References == |
| - | [[Category: Saccharomyces cerevisiae]] | + | <references/> |
| - | [[Category: Desvergne, A.]] | + | __TOC__ |
| - | [[Category: Dufau, L.]] | + | </StructureSection> |
| - | [[Category: Gallastegui, N.]] | + | [[Category: Large Structures]] |
| - | [[Category: Genin, E.]] | + | [[Category: Saccharomyces cerevisiae S288C]] |
| - | [[Category: Groll, M.]] | + | [[Category: Desvergne A]] |
| - | [[Category: Marechal, X.]] | + | [[Category: Dufau L]] |
| - | [[Category: Reboud-Ravaux, M.]] | + | [[Category: Gallastegui N]] |
| - | [[Category: Richy, N.]] | + | [[Category: Genin E]] |
| - | [[Category: Vidal, J.]] | + | [[Category: Groll M]] |
| - | [[Category: Bivalence]]
| + | [[Category: Marechal X]] |
| - | [[Category: Drug discovery]]
| + | [[Category: Reboud-Ravaux M]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | [[Category: Richy N]] |
| - | [[Category: Non-covalent reversible inhibition]]
| + | [[Category: Vidal J]] |
| - | [[Category: Non-lysosomal protein breakdown]]
| + | |
| - | [[Category: Ntn hydrolase]]
| + | |
| - | [[Category: Proteasome]]
| + | |
| - | [[Category: Tmc-95a derivative]]
| + | |
| - | [[Category: Up]]
| + | |
