5jhr

From Proteopedia

(Difference between revisions)

Revision as of 04:07, 4 August 2016

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Yeast 20S proteasome in complex with the peptidic epoxyketone inhibitor 27

Structural highlights

5jhr is a 28 chain structure with sequence from Saccharomyces cerevisiae (strain atcc 204508 / s288c). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	5cz4, 1g65
Activity:	Proteasome endopeptidase complex, with EC number 3.4.25.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Warning: this is a large structure, and loading might take a long time or not happen at all.

Function

[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. [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. [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. [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. [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. [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. [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. [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. [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. [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. [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. [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. [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.^[1] [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.

Publication Abstract from PubMed

This work reports the development of highly potent and selective inhibitors of the beta5c catalytic activity of human constitutive proteasomes. The work describes the design principles, large hydrophobic P3 residue and small hydrophobic P1 residue, that led to the synthesis of a panel of peptide epoxyketones; their evaluation and the selection of the most promising compounds for further analyses. Structure-activity relationships detail how in a logical order the beta1c/i, beta2c/i, and beta5i activities became resistant to inhibition as compounds were diversified stepwise. The most effective compounds were obtained as a mixture of cis- and trans-biscyclohexyl isomers, and enantioselective synthesis resolved this issue. Studies on yeast proteasome structures complexed with some of the compounds provide a rationale for the potency and specificity. Substitution of the N-terminus in the most potent compound for a more soluble equivalent led to a cell-permeable molecule that selectively and efficiently blocks beta5c in cells expressing both constitutive proteasomes and immunoproteasomes.

Structure-Based Design of beta5c Selective Inhibitors of Human Constitutive Proteasomes.,Xin BT, de Bruin G, Huber EM, Besse A, Florea BI, Filippov DV, van der Marel GA, Kisselev AF, van der Stelt M, Driessen C, Groll M, Overkleeft HS J Med Chem. 2016 Aug 1. PMID:27438186^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hilt W, Enenkel C, Gruhler A, Singer T, Wolf DH. The PRE4 gene codes for a subunit of the yeast proteasome necessary for peptidylglutamyl-peptide-hydrolyzing activity. Mutations link the proteasome to stress- and ubiquitin-dependent proteolysis. J Biol Chem. 1993 Feb 15;268(5):3479-86. PMID:8381431
↑ Xin BT, de Bruin G, Huber EM, Besse A, Florea BI, Filippov DV, van der Marel GA, Kisselev AF, van der Stelt M, Driessen C, Groll M, Overkleeft HS. Structure-Based Design of beta5c Selective Inhibitors of Human Constitutive Proteasomes. J Med Chem. 2016 Aug 1. PMID:27438186 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00705

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5jhr"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+{{Large structure}}
+==Yeast 20S proteasome in complex with the peptidic epoxyketone inhibitor 27==
+<StructureSection load='5jhr' size='340' side='right' caption='[[5jhr]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5jhr]] is a 28 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_(strain_atcc_204508_/_s288c) Saccharomyces cerevisiae (strain atcc 204508 / s288c)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JHR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JHR FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6KF:(2S)-2-AZIDO-N-[(2S)-3-(BIPHENYL-4-YL)-1-{[(2S)-1-{[(2S,3S,4R)-3,5-DIHYDROXY-4-METHYLPENTAN-2-YL]AMINO}-1-OXO-3-PHENYLPROPAN-2-YL]AMINO}-1-OXOPROPAN-2-YL]-3-PHENYLPROPANAMIDE+(NON-PREFERRED+NAME)'>6KF</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5cz4|5cz4]], [[1g65|1g65]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5jhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jhr OCA], [http://pdbe.org/5jhr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jhr RCSB], [http://www.ebi.ac.uk/pdbsum/5jhr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jhr ProSAT]</span></td></tr>
+</table>
+{{Large structure}}
+== 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.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+This work reports the development of highly potent and selective inhibitors of the beta5c catalytic activity of human constitutive proteasomes. The work describes the design principles, large hydrophobic P3 residue and small hydrophobic P1 residue, that led to the synthesis of a panel of peptide epoxyketones; their evaluation and the selection of the most promising compounds for further analyses. Structure-activity relationships detail how in a logical order the beta1c/i, beta2c/i, and beta5i activities became resistant to inhibition as compounds were diversified stepwise. The most effective compounds were obtained as a mixture of cis- and trans-biscyclohexyl isomers, and enantioselective synthesis resolved this issue. Studies on yeast proteasome structures complexed with some of the compounds provide a rationale for the potency and specificity. Substitution of the N-terminus in the most potent compound for a more soluble equivalent led to a cell-permeable molecule that selectively and efficiently blocks beta5c in cells expressing both constitutive proteasomes and immunoproteasomes.
-The entry 5jhr is ON HOLD  until Paper Publication
+Structure-Based Design of beta5c Selective Inhibitors of Human Constitutive Proteasomes.,Xin BT, de Bruin G, Huber EM, Besse A, Florea BI, Filippov DV, van der Marel GA, Kisselev AF, van der Stelt M, Driessen C, Groll M, Overkleeft HS J Med Chem. 2016 Aug 1. PMID:27438186<ref>PMID:27438186</ref>
-Authors: Huber, E.M., Groll, M.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: yeast 20S proteasome in complex with the peptidic epoxyketone inhibitor 27
+<div class="pdbe-citations 5jhr" style="background-color:#fffaf0;"></div>
-[[Category: Unreleased Structures]]
+== References ==
-[[Category: Huber, E.M]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Proteasome endopeptidase complex]]
 [[Category: Groll, M]]
+[[Category: Huber, E M]]
+[[Category: Binding analysis]]
+[[Category: Hydrolase-hydrolase inhibitor complex]]
+[[Category: Inhibitor]]
+[[Category: Proteasome]]

5jhr

From Proteopedia

Revision as of 04:07, 4 August 2016

Yeast 20S proteasome in complex with the peptidic epoxyketone inhibitor 27

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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