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TitleOptimization of α-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual inhibitor.
Journal, issue, pagesBioorg Med Chem, Vol. 109, Page 117790, Year 2024
Publish dateJul 15, 2024
AuthorsYuuki Arai / Hiroaki Shitama / Masahito Yamagishi / Satoshi Ono / Akiko Kashima / Masahiro Hiraizumi / Naoki Tsuda / Koushirou Katayama / Kouji Tanaka / Yuzo Koda / Sayuka Kato / Kei Sakata / Osamu Nureki / Hiroshi Miyazaki /
PubMed AbstractThe immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising ...The immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) 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 β5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over β5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-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.
External linksBioorg Med Chem / PubMed:38906067
MethodsEM (single particle)
Resolution2.0 - 2.7 Å
Structure data

39482

8ypk

EMDB-39482, PDB-8ypk:
mouse proteasome 20S subunit in complex with compound 1
Method: EM (single particle) / Resolution: 2.7 Å

39565

8ysx

EMDB-39565, PDB-8ysx:
canine immunoproteasome 20S subunit in complex with compound 2
Method: EM (single particle) / Resolution: 2.2 Å

39600

8yvg

EMDB-39600, PDB-8yvg:
canine immunoproteasome 20S subunit in complex with compound 1
Method: EM (single particle) / Resolution: 2.0 Å

39612

8yvp

EMDB-39612, PDB-8yvp:
canine immunoproteasome 20S subunit in complex with compound 1
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

PDB-1l0c:
Investigation of the Roles of Catalytic Residues in Serotonin N-Acetyltransferase

PDB-1l0d:
X-ray Crystal Structure of AmpC S64D Mutant beta-Lactamase

ChemComp-HOH:
WATER

Source
  • mus musculus (house mouse)
  • canis lupus familiaris (dog)
KeywordsHYDROLASE / Inhibitor / complex / Proteasome / Immunoproteasome

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