View source for 4int


==Yeast 20S proteasome in complex with the vinyl sulfone LU122==
<StructureSection load='4int' size='340' side='right'caption='[[4int]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4int]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4INT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4INT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1G5:HMB-VAL-SER-PHE(4-NH2CH2)-METHYL+VINYL+SULFONE,+BOUND+FORM'>1G5</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4int FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4int OCA], [https://pdbe.org/4int PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4int RCSB], [https://www.ebi.ac.uk/pdbsum/4int PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4int ProSAT]</span></td></tr>
</table>
== Function ==
[https://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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that combinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antineoplastic activity than combinations currently used clinically.

Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites.,Geurink PP, van der Linden WA, Mirabella AC, Gallastegui N, de Bruin G, Blom AE, Voges MJ, Mock ED, Florea BI, van der Marel GA, Driessen C, van der Stelt M, Groll M, Overkleeft HS, Kisselev AF J Med Chem. 2013 Jan 28. PMID:23320547<ref>PMID:23320547</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4int" style="background-color:#fffaf0;"></div>

==See Also==
*[[Proteasome 3D structures|Proteasome 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Saccharomyces cerevisiae]]
[[Category: Blom AEM]]
[[Category: Driessen C]]
[[Category: Florea BI]]
[[Category: Gallastegui N]]
[[Category: Geurink PP]]
[[Category: Groll M]]
[[Category: Kisselev AF]]
[[Category: Mirabella AC]]
[[Category: Mock ED]]
[[Category: Overkleeft HS]]
[[Category: Voges MJ]]
[[Category: De Bruin G]]
[[Category: Van der Linden WA]]
[[Category: Van der Marel GA]]
[[Category: Van der Stelt M]]