4y8h: Difference between revisions
New page: '''Unreleased structure''' The entry 4y8h is ON HOLD Authors: Huber, E.M., Groll, M. Description: Yeast 20S proteasome in complex with N3-APAL-ep Category: Unreleased Structures [[... |
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The | ==Yeast 20S proteasome in complex with N3-APAL-ep== | ||
<StructureSection load='4y8h' size='340' side='right'caption='[[4y8h]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4y8h]] is a 24 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y8H 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]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=05W:(2R,3S,4S)-4-AZANYL-2,6-DIMETHYL-HEPTANE-1,3-DIOL'>05W</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=AZI:AZIDE+ION'>AZI</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=4y8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8h OCA], [https://pdbe.org/4y8h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y8h RCSB], [https://www.ebi.ac.uk/pdbsum/4y8h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y8h ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cleavage analyses of 20S proteasomes with natural or synthetic substrates allowed to infer the substrate specificities of the active sites and paved the way for the rational design of high-affinity proteasome inhibitors. However, details of cleavage preferences remained enigmatic due to the lack of appropriate structural data. In a unique approach, we here systematically examined substrate specificities of yeast and human proteasomes using irreversibly acting alpha',beta'epoxyketone (ep) inhibitors. Biochemical and structural analyses provide unique insights into the substrate preferences of the distinct active sites and highlight differences between proteasome types that may be considered in future inhibitor design efforts. (1) For steric reasons, epoxyketones with Val or Ile at the P1 position are weak inhibitors of all active sites. (2) Identification of the beta2c selective compound Ac-LAE-ep represents a promising starting point for the development of compounds that discriminate between beta2c and beta2i. (3) The compound Ac-LAA-ep was found to favor subunit beta5c over beta5i by three orders of magnitude. (4) Yeast beta1 and human beta1c subunits preferentially bind Asp and Leu in their S1 pockets, while Glu and large hydrophobic residues are not accepted. (5) Exceptional structural features in the beta1/2 substrate binding channel give rise to the beta1 selectivity of compounds featuring Pro at the P3 site. Altogether, 23 different epoxyketone inhibitors, five proteasome mutants, and 43 crystal structures served to delineate a detailed picture of the substrate and ligand specificities of proteasomes and will further guide drug development efforts toward subunit-specific proteasome inhibitors for applications as diverse as cancer and autoimmune disorders. | |||
Systematic Analyses of Substrate Preferences of 20S Proteasomes Using Peptidic Epoxyketone Inhibitors.,Huber EM, de Bruin G, Heinemeyer W, Paniagua Soriano G, Overkleeft HS, Groll M J Am Chem Soc. 2015 Jun 11. PMID:26020686<ref>PMID:26020686</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 4y8h" 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: Synthetic construct]] | |||
[[Category: Groll M]] | |||
[[Category: Huber EM]] | |||
Latest revision as of 12:26, 15 November 2023
Yeast 20S proteasome in complex with N3-APAL-epYeast 20S proteasome in complex with N3-APAL-ep
Structural highlights
FunctionPSB4_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. Publication Abstract from PubMedCleavage analyses of 20S proteasomes with natural or synthetic substrates allowed to infer the substrate specificities of the active sites and paved the way for the rational design of high-affinity proteasome inhibitors. However, details of cleavage preferences remained enigmatic due to the lack of appropriate structural data. In a unique approach, we here systematically examined substrate specificities of yeast and human proteasomes using irreversibly acting alpha',beta'epoxyketone (ep) inhibitors. Biochemical and structural analyses provide unique insights into the substrate preferences of the distinct active sites and highlight differences between proteasome types that may be considered in future inhibitor design efforts. (1) For steric reasons, epoxyketones with Val or Ile at the P1 position are weak inhibitors of all active sites. (2) Identification of the beta2c selective compound Ac-LAE-ep represents a promising starting point for the development of compounds that discriminate between beta2c and beta2i. (3) The compound Ac-LAA-ep was found to favor subunit beta5c over beta5i by three orders of magnitude. (4) Yeast beta1 and human beta1c subunits preferentially bind Asp and Leu in their S1 pockets, while Glu and large hydrophobic residues are not accepted. (5) Exceptional structural features in the beta1/2 substrate binding channel give rise to the beta1 selectivity of compounds featuring Pro at the P3 site. Altogether, 23 different epoxyketone inhibitors, five proteasome mutants, and 43 crystal structures served to delineate a detailed picture of the substrate and ligand specificities of proteasomes and will further guide drug development efforts toward subunit-specific proteasome inhibitors for applications as diverse as cancer and autoimmune disorders. Systematic Analyses of Substrate Preferences of 20S Proteasomes Using Peptidic Epoxyketone Inhibitors.,Huber EM, de Bruin G, Heinemeyer W, Paniagua Soriano G, Overkleeft HS, Groll M J Am Chem Soc. 2015 Jun 11. PMID:26020686[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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