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6htc

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Revision as of 08:00, 24 April 2019

Yeast 20S proteasome with human beta2c (S171G) in complex with ONX 0914

Structural highlights

6htc 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:	PSMB7, Z (HUMAN)
Activity:	Proteasome endopeptidase complex, with EC number 3.4.25.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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. [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. [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. [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. [PSB7_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 unit is responsible of the trypsin-like 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. [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] [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. [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

Subunit-selective proteasome inhibitors are valuable tools to assess the biological function and medicinal relevance of individual proteasome active sites in a specific context. While inhibitors for the beta1c, beta1i, beta5c and beta5i subunits exploit structural differences in the substrate binding channels identified by X-ray crystallography, compounds selectively targeting beta2c or beta2i could not be rationally designed so far due to the high degree of structural similarity of these subunits. Here we report the development, chemical synthesis and biological screening of a compound library that led to the identification of the beta2c- and beta2i-selective compounds LU-002c (4; IC50 beta2c: 8 nM, IC50 beta2i/beta2c: 20-fold) and LU-002i (5; IC50 beta2i: 220 nM, IC50 beta2c/beta2i: 45-fold), respectively. Co-crystal structures with beta2-humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, an elaborate combination of organic syntheses, activity-based protein profiling, yeast mutagenesis and structural biology allowed us to decipher subtle but significant differences of beta2 substrate binding channels and to complete the set of subunit-selective proteasome inhibitors by identifying beta2c- and beta2i-selective compounds.

Structure-based design of inhibitors selective for human proteasome beta2c or beta2i subunits.,Xin BT, Huber E, de Bruin G, Heinemeyer W, Maurits E, Espinal C, Du Y, Janssens M, Weyburne ES, Kisselev A, Florea BI, Driessen C, van der Marel GA, Groll M, Overkleeft HS J Med Chem. 2019 Jan 18. doi: 10.1021/acs.jmedchem.8b01884. PMID:30657666^[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, Huber E, de Bruin G, Heinemeyer W, Maurits E, Espinal C, Du Y, Janssens M, Weyburne ES, Kisselev A, Florea BI, Driessen C, van der Marel GA, Groll M, Overkleeft HS. Structure-based design of inhibitors selective for human proteasome beta2c or beta2i subunits. J Med Chem. 2019 Jan 18. doi: 10.1021/acs.jmedchem.8b01884. PMID:30657666 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01884

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/6htc"

@@ Line 1: / Line 1: @@
 ==Yeast 20S proteasome with human beta2c (S171G) in complex with ONX 0914==
-<StructureSection load='6htc' size='340' side='right' caption='[[6htc]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='6htc' size='340' side='right'caption='[[6htc]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6htc]] 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=6HTC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HTC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6htc]] 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=6HTC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HTC FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GQK:(2~{S})-3-(4-methoxyphenyl)-~{N}-[(2~{S},3~{R})-4-methyl-3,4-bis(oxidanyl)-1-phenyl-pentan-2-yl]-2-[[(2~{S})-2-(2-morpholin-4-ylethanoylamino)propanoyl]amino]propanamide'>GQK</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">PSMB7, Z ([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=6htc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6htc OCA], [http://pdbe.org/6htc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6htc RCSB], [http://www.ebi.ac.uk/pdbsum/6htc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6htc ProSAT]</span></td></tr>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Baker's yeast]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Proteasome endopeptidase complex]]
 [[Category: Groll, M]]

6htc

From Proteopedia

Revision as of 08:00, 24 April 2019

Yeast 20S proteasome with human beta2c (S171G) in complex with ONX 0914

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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