9yuz: Difference between revisions
From Proteopedia
Jump to navigationJump to search
m Protected "9yuz" [edit=sysop:move=sysop] |
No edit summary |
||
| (One intermediate revision by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Structure of the human 20S proteasome in complex with a beta5-selective covalent syringolin analogue inhibitor.== | ||
<StructureSection load='9yuz' size='340' side='right'caption='[[9yuz]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9yuz]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9YUZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9YUZ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CY5:methyl+(2~{S})-2-[[(2~{R})-1-[[(5~{R},8~{S})-5-[(3-fluorophenyl)methyl]-2,7-bis(oxidanylidene)-1,6-diazacyclododec-8-yl]amino]-1-oxidanylidene-3-phenyl-propan-2-yl]carbamoylamino]-3-methyl-butanoate'>A1CY5</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=9yuz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9yuz OCA], [https://pdbe.org/9yuz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9yuz RCSB], [https://www.ebi.ac.uk/pdbsum/9yuz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9yuz ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PSA2_HUMAN PSA2_HUMAN] The proteasome is a multicatalytic proteinase complex which 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. The proteasome has an ATP-dependent proteolytic activity. PSMA2 may have a potential regulatory effect on another component(s) of the proteasome complex through tyrosine phosphorylation. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The syringolin natural products are covalent inhibitors of the 20S proteasome that inspire therapeutic development. Here, we report a new route to the syringolins amenable to solution and solid-phase synthesis that overcomes a problematic macrocyclization. Exploiting our synthetic approach and substrate mimicry models for proteasome inhibition by the syringolins, we generated a collection of hypothetically selective inhibitors of the Plasmodium falciparum proteasome, which is an emerging target for antimalarial drugs. We identified compounds from the library having high second-order rate constants for Plasmodium proteasome inhibition and nanomolar antiparasitic activity. They exhibited selectivity for the Plasmodium proteasome over the human proteasome. We solved cryo-EM structures of an inhibitor bound to both 20S proteasomes, revealing key contacts favoring species-selective inhibition. Together, this work provides an improved route to syringolin analogs, sheds new light on substrate mimicry by the syringolins, and provides a structural basis for the pursuit of new antimalarial drugs. | |||
An Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the Plasmodium falciparum 20S Proteasome.,Gu X, Fajtova P, Yan NL, Saxena A, Fei F, Zhu J, Tse E, Melo A, Yoo E, Buchwald NH, Southworth DR, Bogyo M, Derisi JL, Gestwicki JE, O'Donoghue AJ, Sello JK J Med Chem. 2026 Apr 1. doi: 10.1021/acs.jmedchem.5c03223. PMID:41921688<ref>PMID:41921688</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 9yuz" style="background-color:#fffaf0;"></div> | ||
[[Category: Gestwicki | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: O | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Fajtova P]] | ||
[[Category: | [[Category: Gestwicki JE]] | ||
[[Category: Gu X]] | |||
[[Category: Melo A]] | |||
[[Category: O'Donoghue A]] | |||
[[Category: Sello JK]] | |||
[[Category: Southworth DR]] | |||
[[Category: Tse E]] | |||
[[Category: Yan NL]] | |||
