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==== | ==Yeast 20S proteasome in complex with glidobactin-like natural product HB333== | ||
<StructureSection load='6zou' size='340' side='right'caption='[[6zou]]' scene=''> | <StructureSection load='6zou' size='340' side='right'caption='[[6zou]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[6zou]] 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=6ZOU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZOU FirstGlance]. <br> | ||
</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=6zou FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zou OCA], [https://pdbe.org/6zou PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zou RCSB], [https://www.ebi.ac.uk/pdbsum/6zou PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zou ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=QOH:11-methyl-~{N}-[(2~{S},3~{R})-1-[[(5~{S},8~{S},10~{S})-5-methyl-10-oxidanyl-2,7-bis(oxidanylidene)-1,6-diazacyclododec-8-yl]amino]-3-oxidanyl-1-oxidanylidene-butan-2-yl]dodecanamide'>QOH</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=6zou FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zou OCA], [https://pdbe.org/6zou PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zou RCSB], [https://www.ebi.ac.uk/pdbsum/6zou PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zou ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
The glidobactin-like natural products (GLNPs) glidobactin A and cepafungin I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881-1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli. Their chemical diversity results from a relaxed substrate specificity and flexible product release in the assembly line of GLNPs. Crystal structure analysis of the yeast proteasome in complex with new GLNPs suggests that the degree of unsaturation and the length of the aliphatic tail are critical for their bioactivity. The results in this study provide the basis to engineer the BGC for the generation of new GLNPs and to optimize these natural products resulting in potential drugs for cancer therapy. | |||
Activation, Structure, Biosynthesis and Bioactivity of Glidobactin-like Proteasome Inhibitors from Photorhabdus laumondii.,Zhao L, Le Chapelain C, Brachmann AO, Kaiser M, Groll M, Bode HB Chembiochem. 2021 May 4;22(9):1582-1588. doi: 10.1002/cbic.202100014. Epub 2021 , Mar 3. PMID:33452852<ref>PMID:33452852</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6zou" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Proteasome 3D structures|Proteasome 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Saccharomyces cerevisiae S288C]] | ||
[[Category: Bode HB]] | |||
[[Category: Brachmann AO]] | |||
[[Category: Groll M]] | |||
[[Category: Kaiser M]] | |||
[[Category: Le Chapelain C]] | |||
[[Category: Zhao L]] | |||
Latest revision as of 14:55, 1 February 2024
Yeast 20S proteasome in complex with glidobactin-like natural product HB333Yeast 20S proteasome in complex with glidobactin-like natural product HB333
Structural highlights
FunctionPSA2_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 PubMedThe glidobactin-like natural products (GLNPs) glidobactin A and cepafungin I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881-1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli. Their chemical diversity results from a relaxed substrate specificity and flexible product release in the assembly line of GLNPs. Crystal structure analysis of the yeast proteasome in complex with new GLNPs suggests that the degree of unsaturation and the length of the aliphatic tail are critical for their bioactivity. The results in this study provide the basis to engineer the BGC for the generation of new GLNPs and to optimize these natural products resulting in potential drugs for cancer therapy. Activation, Structure, Biosynthesis and Bioactivity of Glidobactin-like Proteasome Inhibitors from Photorhabdus laumondii.,Zhao L, Le Chapelain C, Brachmann AO, Kaiser M, Groll M, Bode HB Chembiochem. 2021 May 4;22(9):1582-1588. doi: 10.1002/cbic.202100014. Epub 2021 , Mar 3. PMID:33452852[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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