|
|
| Line 1: |
Line 1: |
|
| |
|
| ==Yeast 20S proteasome in complex with the dimerized linear mimetic of TMC-95A - yCP:4a== | | ==Yeast 20S proteasome in complex with the dimerized linear mimetic of TMC-95A - yCP:4a== |
| <StructureSection load='4jt0' size='340' side='right'caption='[[4jt0]], [[Resolution|resolution]] 3.10Å' scene=''> | | <StructureSection load='4jt0' size='340' side='right'caption='[[4jt0]]' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4jt0]] is a 30 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JT0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JT0 FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JT0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JT0 FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0L1:HEXANEDIOIC+ACID'>0L1</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr> | | </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=4jt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jt0 OCA], [https://pdbe.org/4jt0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jt0 RCSB], [https://www.ebi.ac.uk/pdbsum/4jt0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jt0 ProSAT]</span></td></tr> |
| <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ABN:BENZYLAMINE'>ABN</scene>, <scene name='pdbligand=ACA:6-AMINOHEXANOIC+ACID'>ACA</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1jd2|1jd2]], [[4jsq|4jsq]], [[4jsu|4jsu]]</div></td></tr>
| |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex Proteasome endopeptidase complex], with EC number [https://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=4jt0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jt0 OCA], [https://pdbe.org/4jt0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jt0 RCSB], [https://www.ebi.ac.uk/pdbsum/4jt0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jt0 ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Function ==
| |
| [[https://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. [[https://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. [[https://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. [[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. [[https://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> [[https://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. [[https://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. [[https://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. [[https://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. [[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. [[https://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. [[https://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. [[https://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. [[https://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.
| |
| <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.
| |
|
| |
| 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>
| |
|
| |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| |
| </div>
| |
| <div class="pdbe-citations 4jt0" style="background-color:#fffaf0;"></div>
| |
|
| |
|
| ==See Also== | | ==See Also== |
| *[[Proteasome 3D structures|Proteasome 3D structures]] | | *[[Proteasome 3D structures|Proteasome 3D structures]] |
| == References ==
| |
| <references/>
| |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Proteasome endopeptidase complex]]
| | [[Category: Desvergne A]] |
| [[Category: Saccharomyces cerevisiae]]
| | [[Category: Dufau L]] |
| [[Category: Desvergne, A]] | | [[Category: Gallastegui N]] |
| [[Category: Dufau, L]] | | [[Category: Genin E]] |
| [[Category: Gallastegui, N]] | | [[Category: Groll M]] |
| [[Category: Genin, E]] | | [[Category: Marechal X]] |
| [[Category: Groll, M]] | | [[Category: Reboud-Ravaux M]] |
| [[Category: Marechal, X]] | | [[Category: Richy N]] |
| [[Category: Reboud-Ravaux, M]] | | [[Category: Vidal J]] |
| [[Category: Richy, N]] | |
| [[Category: Vidal, J]] | |
| [[Category: Bivalence]]
| |
| [[Category: Drug discovery]]
| |
| [[Category: Hydrolase-hydrolase inhibitor complex]]
| |
| [[Category: Non-covalent reversible inhibition]]
| |
| [[Category: Non-lysosomal protein breakdown]]
| |
| [[Category: Ntn hydrolase]]
| |
| [[Category: Proteasome]]
| |
| [[Category: Tmc-95a derivative]]
| |
| [[Category: Up]]
| |