4eu2

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==Crystal structure of 20s proteasome with novel inhibitor K-7174==
==Crystal structure of 20s proteasome with novel inhibitor K-7174==
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<StructureSection load='4eu2' size='340' side='right' caption='[[4eu2]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
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<StructureSection load='4eu2' size='340' side='right'caption='[[4eu2]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4eu2]] 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=4EU2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EU2 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4eu2]] 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=4EU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EU2 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=WPI:1,4-BIS[(4E)-5-(3,4,5-TRIMETHOXYPHENYL)PENT-4-EN-1-YL]-1,4-DIAZEPANE'>WPI</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.509&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WPI:1,4-BIS[(4E)-5-(3,4,5-TRIMETHOXYPHENYL)PENT-4-EN-1-YL]-1,4-DIAZEPANE'>WPI</scene></td></tr>
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<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=4eu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eu2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4eu2 RCSB], [http://www.ebi.ac.uk/pdbsum/4eu2 PDBsum]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4eu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4eu2 OCA], [https://pdbe.org/4eu2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4eu2 RCSB], [https://www.ebi.ac.uk/pdbsum/4eu2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4eu2 ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://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.
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The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ss 1, ss 2 and ss 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ss5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ss5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.
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Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.,Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, Furukawa Y PLoS One. 2013 Apr 11;8(4):e60649. doi: 10.1371/journal.pone.0060649. Print 2013. PMID:23593271<ref>PMID:23593271</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Proteasome|Proteasome]]
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*[[Proteasome 3D structures|Proteasome 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Proteasome endopeptidase complex]]
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[[Category: Large Structures]]
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[[Category: Saccharomyces cerevisiae]]
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[[Category: Saccharomyces cerevisiae S288C]]
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[[Category: Akutsu, M]]
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[[Category: Akutsu M]]
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[[Category: Furukawa, Y]]
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[[Category: Furukawa Y]]
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[[Category: Izumi, T]]
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[[Category: Izumi T]]
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[[Category: Kano, Y]]
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[[Category: Kano Y]]
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[[Category: Kikuchi, J]]
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[[Category: Kikuchi J]]
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[[Category: Nobuyoshi, M]]
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[[Category: Nobuyoshi M]]
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[[Category: Ohki, M]]
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[[Category: Ohki M]]
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[[Category: Park, S Y]]
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[[Category: Park S-Y]]
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[[Category: Shibayama, N]]
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[[Category: Shibayama N]]
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[[Category: Sugiyama, K]]
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[[Category: Sugiyama K]]
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[[Category: Wada, T]]
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[[Category: Wada T]]
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[[Category: Yamada, S]]
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[[Category: Yamada S]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Proteasome inhibitor]]
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Current revision

Crystal structure of 20s proteasome with novel inhibitor K-7174

PDB ID 4eu2

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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