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5l5v

From Proteopedia

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Revision as of 10:35, 12 August 2020

'Yeast 20S proteasome with human beta5i (1-138; V31M) and human beta6 (97-111; 118-133) in complex with epoxyketone inhibitor 18

Structural highlights

5l5v is a 28 chain structure with sequence from Baker's yeast and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5cz4
Gene:	PRE2, DOA3, PRG1, YPR103W, P8283.10 (HUMAN), PRE7, PRS3, PTS1, YBL041W, YBL0407 (HUMAN)
Activity:	Proteasome endopeptidase complex, with EC number 3.4.25.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PSB8_HUMAN] CANDLE syndrome;Nakajo-Nishimura syndrome;JMP syndrome. The disease is caused by mutations affecting the gene represented in this entry.

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. [PSB8_HUMAN] The proteasome is a multicatalytic proteinase complex which 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. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.^[1] ^[2] ^[3] ^[4] [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. [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. [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. [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.^[5] [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

Inhibition of the immunoproteasome subunit beta5i alleviates autoimmune diseases in preclinical studies and represents a promising new anti-inflammatory therapy. However, the lack of structural data on the human immunoproteasome still hampers drug design. Here, we systematically determined the potency of seven alpha' beta' epoxyketone inhibitors with varying N-caps and P3-stereochemistry for mouse/human beta5c/beta5i and found pronounced differences in their subunit and species selectivity. Using X-ray crystallography, the compounds were analyzed for their modes of binding to chimeric yeast proteasomes that incorporate key parts of human beta5c, human beta5i or mouse beta5i and the neighboring beta6 subunit. The structural data reveal exceptional conformations for the most selective human beta5i inhibitors and highlight subtle structural differences as the major reason for the observed species selectivity. Altogether, the presented results validate the humanized yeast proteasome as a powerful tool for structure-based development of beta5i inhibitors with potential clinical applications.

A humanized yeast proteasome identifies unique binding modes of inhibitors for the immunosubunit beta5i.,Huber EM, Heinemeyer W, de Bruin G, Overkleeft HS, Groll M EMBO J. 2016 Dec 1;35(23):2602-2613. Epub 2016 Oct 27. PMID:27789522^[6]

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

References

↑ Heink S, Fricke B, Ludwig D, Kloetzel PM, Kruger E. Tumor cell lines expressing the proteasome subunit isoform LMP7E1 exhibit immunoproteasome deficiency. Cancer Res. 2006 Jan 15;66(2):649-52. PMID:16423992 doi:http://dx.doi.org/10.1158/0008-5472.CAN-05-2872
↑ Yang Z, Gagarin D, St Laurent G 3rd, Hammell N, Toma I, Hu CA, Iwasa A, McCaffrey TA. Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome. Arterioscler Thromb Vasc Biol. 2009 Aug;29(8):1213-9. doi:, 10.1161/ATVBAHA.109.189407. Epub 2009 May 14. PMID:19443843 doi:http://dx.doi.org/10.1161/ATVBAHA.109.189407
↑ Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishizawa M, Toyoshima Y, Takahashi H, Standley DM, Tanaka K, Hamazaki J, Murata S, Obara K, Toyoshima I, Yasutomo K. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest. 2011 Oct;121(10):4150-60. doi: 10.1172/JCI58414. Epub 2011 Sep 1. PMID:21881205 doi:http://dx.doi.org/10.1172/JCI58414
↑ Akiyama K, Kagawa S, Tamura T, Shimbara N, Takashina M, Kristensen P, Hendil KB, Tanaka K, Ichihara A. Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced by interferon-gamma for acquirement of the functional diversity responsible for antigen processing. FEBS Lett. 1994 Apr 18;343(1):85-8. PMID:8163024
↑ 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
↑ Huber EM, Heinemeyer W, de Bruin G, Overkleeft HS, Groll M. A humanized yeast proteasome identifies unique binding modes of inhibitors for the immunosubunit beta5i. EMBO J. 2016 Dec 1;35(23):2602-2613. Epub 2016 Oct 27. PMID:27789522 doi:http://dx.doi.org/10.15252/embj.201695222

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5l5v"

@@ Line 1: / Line 1: @@
-{{Large structure}}
 =='Yeast 20S proteasome with human beta5i (1-138; V31M) and human beta6 (97-111; 118-133) in complex with epoxyketone inhibitor 18==
-<StructureSection load='5l5v' size='340' side='right' caption='[[5l5v]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+<StructureSection load='5l5v' size='340' side='right'caption='[[5l5v]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5l5v]] is a 28 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [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=5L5V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L5V FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5l5v]] is a 28 chain structure with sequence from [http://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L5V OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5L5V FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6NV:~{N}-[(2~{R})-1-[[(2~{S})-3-(4-methoxyphenyl)-1-[[(2~{S},3~{S},4~{R})-4-methyl-3,5-bis(oxidanyl)-1-phenyl-pentan-2-yl]amino]-1-oxidanylidene-propan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-1-methyl-5~{H}-indene-2-carboxamide'>6NV</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6NV:~{N}-[(2~{R})-1-[[(2~{S})-3-(4-methoxyphenyl)-1-[[(2~{S},3~{S},4~{R})-4-methyl-3,5-bis(oxidanyl)-1-phenyl-pentan-2-yl]amino]-1-oxidanylidene-propan-2-yl]amino]-1-oxidanylidene-propan-2-yl]-1-methyl-5~{H}-indene-2-carboxamide'>6NV</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRE2, DOA3, PRG1, YPR103W, P8283.10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), PRE7, PRS3, PTS1, YBL041W, YBL0407 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5l5v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l5v OCA], [http://pdbe.org/5l5v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l5v RCSB], [http://www.ebi.ac.uk/pdbsum/5l5v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l5v ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5l5v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l5v OCA], [http://pdbe.org/5l5v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l5v RCSB], [http://www.ebi.ac.uk/pdbsum/5l5v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l5v ProSAT]</span></td></tr>
 </table>
-{{Large structure}}
 == Disease ==
 [[http://www.uniprot.org/uniprot/PSB8_HUMAN PSB8_HUMAN]] CANDLE syndrome;Nakajo-Nishimura syndrome;JMP syndrome. The disease is caused by mutations affecting the gene represented in this entry.
@@ Line 23: / Line 23: @@
 </div>
 <div class="pdbe-citations 5l5v" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Proteasome 3D structures|Proteasome 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Baker's yeast]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Proteasome endopeptidase complex]]
 [[Category: Groll, M]]

5l5v

From Proteopedia

Revision as of 10:35, 12 August 2020

'Yeast 20S proteasome with human beta5i (1-138; V31M) and human beta6 (97-111; 118-133) in complex with epoxyketone inhibitor 18

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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