View source for 8yvg


==canine immunoproteasome 20S subunit in complex with compound 1==
<StructureSection load='8yvg' size='340' side='right'caption='[[8yvg]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8yvg]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Canis_lupus_familiaris Canis lupus familiaris]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8YVG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8YVG 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L0C:[(2~{R},3~{S})-3-azanyl-4-oxidanylidene-butan-2-yl]oxy-[(1~{R})-1-[(1-cyclohexyl-1,2,3-triazol-4-yl)carbonylamino]-3-methyl-butyl]-$l^{3}-oxidanyl-oxidanyl-boron'>A1L0C</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=8yvg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8yvg OCA], [https://pdbe.org/8yvg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8yvg RCSB], [https://www.ebi.ac.uk/pdbsum/8yvg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8yvg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A8C0NHD1_CANLF A0A8C0NHD1_CANLF] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The immunoproteasome subunit LMP7 (beta5i)/LMP2 (beta1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit beta5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over beta5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of alpha-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor 19. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with 19 explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that 19 is orally bioavailable and shows promise as potential treatment for autoimmune diseases.

Optimization of alpha-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (beta5i)/LMP2 (beta1i) dual inhibitor.,Arai Y, Shitama H, Yamagishi M, Ono S, Kashima A, Hiraizumi M, Tsuda N, Katayama K, Tanaka K, Koda Y, Kato S, Sakata K, Nureki O, Miyazaki H Bioorg Med Chem. 2024 Jul 15;109:117790. doi: 10.1016/j.bmc.2024.117790. Epub , 2024 Jun 12. PMID:38906067<ref>PMID:38906067</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8yvg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Canis lupus familiaris]]
[[Category: Large Structures]]
[[Category: Arai Y]]
[[Category: Kashima A]]