5ltt: Difference between revisions
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The | ==Yeast 20S proteasome with human beta5i (1-138; R57T)in complex with PR-924== | ||
<StructureSection load='5ltt' size='340' side='right'caption='[[5ltt]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ltt]] 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=5LTT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LTT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=39V:N-[(3-METHYL-1H-INDEN-2-YL)CARBONYL]-D-ALANYL-N-[(2S,4R)-5-HYDROXY-4-METHYL-3-OXO-1-PHENYLPENTAN-2-YL]-L-TRYPTOPHANAMIDE'>39V</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5ltt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ltt OCA], [https://pdbe.org/5ltt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ltt RCSB], [https://www.ebi.ac.uk/pdbsum/5ltt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ltt 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 == | |||
Inhibition of the immunoproteasome subunit beta5i alleviates autoimmune diseases in preclinical studies and represents a promising new anti-inflammatory therapy. However, the lack of structural data on the human immunoproteasome still hampers drug design. Here, we systematically determined the potency of seven alpha' beta' epoxyketone inhibitors with varying N-caps and P3-stereochemistry for mouse/human beta5c/beta5i and found pronounced differences in their subunit and species selectivity. Using X-ray crystallography, the compounds were analyzed for their modes of binding to chimeric yeast proteasomes that incorporate key parts of human beta5c, human beta5i or mouse beta5i and the neighboring beta6 subunit. The structural data reveal exceptional conformations for the most selective human beta5i inhibitors and highlight subtle structural differences as the major reason for the observed species selectivity. Altogether, the presented results validate the humanized yeast proteasome as a powerful tool for structure-based development of beta5i inhibitors with potential clinical applications. | |||
A humanized yeast proteasome identifies unique binding modes of inhibitors for the immunosubunit beta5i.,Huber EM, Heinemeyer W, de Bruin G, Overkleeft HS, Groll M EMBO J. 2016 Dec 1;35(23):2602-2613. Epub 2016 Oct 27. PMID:27789522<ref>PMID:27789522</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5ltt" style="background-color:#fffaf0;"></div> | ||
[[Category: Groll | |||
==See Also== | |||
*[[Proteasome 3D structures|Proteasome 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Saccharomyces cerevisiae S288C]] | |||
[[Category: Groll M]] | |||
[[Category: Huber EM]] | |||
Latest revision as of 21:49, 18 October 2023
Yeast 20S proteasome with human beta5i (1-138; R57T)in complex with PR-924Yeast 20S proteasome with human beta5i (1-138; R57T)in complex with PR-924
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 PubMedInhibition of the immunoproteasome subunit beta5i alleviates autoimmune diseases in preclinical studies and represents a promising new anti-inflammatory therapy. However, the lack of structural data on the human immunoproteasome still hampers drug design. Here, we systematically determined the potency of seven alpha' beta' epoxyketone inhibitors with varying N-caps and P3-stereochemistry for mouse/human beta5c/beta5i and found pronounced differences in their subunit and species selectivity. Using X-ray crystallography, the compounds were analyzed for their modes of binding to chimeric yeast proteasomes that incorporate key parts of human beta5c, human beta5i or mouse beta5i and the neighboring beta6 subunit. The structural data reveal exceptional conformations for the most selective human beta5i inhibitors and highlight subtle structural differences as the major reason for the observed species selectivity. Altogether, the presented results validate the humanized yeast proteasome as a powerful tool for structure-based development of beta5i inhibitors with potential clinical applications. A humanized yeast proteasome identifies unique binding modes of inhibitors for the immunosubunit beta5i.,Huber EM, Heinemeyer W, de Bruin G, Overkleeft HS, Groll M EMBO J. 2016 Dec 1;35(23):2602-2613. Epub 2016 Oct 27. PMID:27789522[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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