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==yCP beta5-C63F mutant in complex with bortezomib== | ==yCP beta5-C63F mutant in complex with bortezomib== | ||
<StructureSection load='4qw3' size='340' side='right' caption='[[4qw3]], [[Resolution|resolution]] 2.90Å' scene=''> | <StructureSection load='4qw3' size='340' side='right'caption='[[4qw3]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4qw3]] is a 28 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QW3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QW3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4qw3]] 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/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QW3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QW3 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BO2:N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE'>BO2</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"><scene name='pdbligand=BO2:N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE'>BO2</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">[[4qtr|4qtr]], [[4qux|4qux]], [[4quy|4quy]], [[4qv0|4qv0]], [[4qv1|4qv1]], [[4qv3|4qv3]], [[4qv4|4qv4]], [[4qv5|4qv5]], [[4qv6|4qv6]], [[4qv7|4qv7]], [[4qv8|4qv8]], [[4qv9|4qv9]], [[4qvl|4qvl]], [[4qvm|4qvm]], [[4qvn|4qvn]], [[4qvp|4qvp]], [[4qvq|4qvq]], [[1ryp|1ryp]], [[4qwr|4qwr]], [[4qws|4qws]], [[4qwu|4qwu]], [[4qwx|4qwx]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qtr|4qtr]], [[4qux|4qux]], [[4quy|4quy]], [[4qv0|4qv0]], [[4qv1|4qv1]], [[4qv3|4qv3]], [[4qv4|4qv4]], [[4qv5|4qv5]], [[4qv6|4qv6]], [[4qv7|4qv7]], [[4qv8|4qv8]], [[4qv9|4qv9]], [[4qvl|4qvl]], [[4qvm|4qvm]], [[4qvn|4qvn]], [[4qvp|4qvp]], [[4qvq|4qvq]], [[1ryp|1ryp]], [[4qwr|4qwr]], [[4qws|4qws]], [[4qwu|4qwu]], [[4qwx|4qwx]]</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=559292 Baker's yeast])</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='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=4qw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qw3 OCA], [http://pdbe.org/4qw3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qw3 RCSB], [http://www.ebi.ac.uk/pdbsum/4qw3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qw3 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=4qw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qw3 OCA], [http://pdbe.org/4qw3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qw3 RCSB], [http://www.ebi.ac.uk/pdbsum/4qw3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qw3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== 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/ | [[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/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/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/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/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/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/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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Baker's yeast]] | |||
[[Category: Large Structures]] | |||
[[Category: Proteasome endopeptidase complex]] | [[Category: Proteasome endopeptidase complex]] | ||
[[Category: Saccharomyces cerevisiae]] | [[Category: Saccharomyces cerevisiae]] | ||
Revision as of 12:08, 24 April 2019
yCP beta5-C63F mutant in complex with bortezomibyCP beta5-C63F mutant in complex with bortezomib
Structural highlights
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. [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. [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 PubMedInhibition of the 20S proteasome by bortezomib (Velcade) constitutes a successfully applied therapy for blood cancer. However, emerging resistance restricts its medicinal use. For example, mutations in the proteolytically active beta5-subunit of the proteasome, the main target of inhibitors, were reported to impair drug binding and thus to reduce therapeutic efficacy. Using yeast as a model system, we describe here a systematic evaluation of these mutations by cell growth analysis, proteasome inhibition assays, and X-ray crystallography. The 11 mutants examined display decreased proliferation rates, impaired proteolytic activity, and marked resistance to bortezomib as well as the alpha',beta'-epoxyketone inhibitors carfilzomib (Kyprolis) and ONX 0914, while the second-generation compound carfilzomib was the least affected. In total, 49 proteasome X-ray structures, including structural data on proteasome-carfilzomib complexes, reveal three distinct molecular mechanisms that hamper both drug binding and natural substrate turnover to an extent that is still compatible with cell survival. Bortezomib-Resistant Mutant Proteasomes: Structural and Biochemical Evaluation with Carfilzomib and ONX 0914.,Huber EM, Heinemeyer W, Groll M Structure. 2015 Feb 3;23(2):407-17. doi: 10.1016/j.str.2014.11.019. Epub 2015 Jan, 15. PMID:25599643[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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