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| - | {{Large structure}}
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| | ==yCP in complex with tripeptidic epoxyketone inhibitor 9== | | ==yCP in complex with tripeptidic epoxyketone inhibitor 9== |
| - | <StructureSection load='4qlu' size='340' side='right' caption='[[4qlu]], [[Resolution|resolution]] 2.80Å' scene=''> | + | <StructureSection load='4qlu' size='340' side='right'caption='[[4qlu]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qlu]] is a 28 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=4QLU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QLU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qlu]] 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=4QLU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QLU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=38X:N-[(3-METHYL-1H-INDEN-2-YL)CARBONYL]-D-ALANYL-N-[(2S,4R)-1-CYCLOHEXYL-5-HYDROXY-4-METHYL-3-OXOPENTAN-2-YL]-L-TRYPTOPHANAMIDE'>38X</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]], [[1g65|1g65]], [[4qlq|4qlq]], [[4qls|4qls]], [[4qlt|4qlt]], [[4qlv|4qlv]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=38X:N-[(3-METHYL-1H-INDEN-2-YL)CARBONYL]-D-ALANYL-N-[(2S,4R)-1-CYCLOHEXYL-5-HYDROXY-4-METHYL-3-OXOPENTAN-2-YL]-L-TRYPTOPHANAMIDE'>38X</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=4qlu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qlu OCA], [https://pdbe.org/4qlu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qlu RCSB], [https://www.ebi.ac.uk/pdbsum/4qlu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qlu 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=4qlu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qlu OCA], [http://pdbe.org/4qlu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qlu RCSB], [http://www.ebi.ac.uk/pdbsum/4qlu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qlu ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | {{Large structure}} | |
| | == Function == | | == Function == |
| - | [[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/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/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/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. | + | [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. |
| | <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== |
| - | *[[Proteasome|Proteasome]] | + | *[[Proteasome 3D structures|Proteasome 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Proteasome endopeptidase complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Saccharomyces cerevisiae]] | + | [[Category: Saccharomyces cerevisiae S288C]] |
| - | [[Category: Al-Ayed, K]] | + | [[Category: Al-Ayed K]] |
| - | [[Category: Bruin, G de]]
| + | [[Category: Driessen C]] |
| - | [[Category: Driessen, C]] | + | [[Category: Groll M]] |
| - | [[Category: Groll, M]] | + | [[Category: Huber E]] |
| - | [[Category: Huber, E]] | + | [[Category: Kim K]] |
| - | [[Category: Kim, K]] | + | [[Category: Kisselev A]] |
| - | [[Category: Kisselev, A]] | + | [[Category: Overkleeft H]] |
| - | [[Category: Marel, G van der]]
| + | [[Category: Xin B]] |
| - | [[Category: Overkleeft, H]] | + | [[Category: De Bruin G]] |
| - | [[Category: Rooden, E van]]
| + | [[Category: Van Rooden E]] |
| - | [[Category: Xin, B]] | + | [[Category: Van der Marel G]] |
| - | [[Category: Binding analysis]] | + | |
| - | [[Category: Epoxyketone]] | + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]] | + | |
| - | [[Category: Immunoproteasome inhibitor]]
| + | |
| - | [[Category: Proteasome]]
| + | |
| Structural highlights
Function
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.
Publication Abstract from PubMed
Mammalian genomes encode seven catalytic proteasome subunits, namely, beta1c, beta2c, beta5c (assembled into constitutive 20S proteasome core particles), beta1i, beta2i, beta5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit beta5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of beta1c/beta1i, beta2c/beta2i, or beta5c/beta5i are available, yet ligands truly selective for a single proteasome activity are scarce. In this work we report the development of cell-permeable beta1i and beta5i selective inhibitors that outperform existing leads in terms of selectivity and/or potency. These compounds are the result of a rational design strategy using known inhibitors as starting points and introducing structural features according to the X-ray structures of the murine constitutive and immunoproteasome 20S core particles.
Structure-Based Design of beta1i or beta5i Specific Inhibitors of Human Immunoproteasomes.,de Bruin G, Huber EM, Xin BT, van Rooden EJ, Al-Ayed K, Kim KB, Kisselev AF, Driessen C, van der Stelt M, van der Marel GA, Groll M, Overkleeft HS J Med Chem. 2014 Jul 15. PMID:25006746[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ de Bruin G, Huber EM, Xin BT, van Rooden EJ, Al-Ayed K, Kim KB, Kisselev AF, Driessen C, van der Stelt M, van der Marel GA, Groll M, Overkleeft HS. Structure-Based Design of beta1i or beta5i Specific Inhibitors of Human Immunoproteasomes. J Med Chem. 2014 Jul 15. PMID:25006746 doi:http://dx.doi.org/10.1021/jm500716s
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