PDBsum entry 5cgi

Hydrolase/hydrolase inhibitor

PDB id: 5cgi

Contents

Protein chains

250 a.a.

244 a.a.

240 a.a.

235 a.a.

231 a.a.

243 a.a.

241 a.a.

222 a.a.

204 a.a.

195 a.a.

212 a.a.

222 a.a.

233 a.a.

196 a.a.

Ligands

MES ×4

04C ×6

Metals

_CL ×2

_MG ×8

_NA ×2

Waters ×266

PDB id:

5cgi

Name:

Hydrolase/hydrolase inhibitor

Title:

Yeast 20s proteasome beta5-g48c mutant in complex with onx 0914

Structure:

Proteasome subunit alpha type-2. Chain: a, o. Synonym: macropain subunit y7,multicatalytic endopeptidase complex subunit y7,proteasome component y7,proteinase ysce subunit 7. Proteasome subunit alpha type-3. Chain: b, p. Synonym: macropain subunit y13,multicatalytic endopeptidase complex subunit y13,proteasome component y13,proteinase ysce subunit 13. Proteasome subunit alpha type-4.

Source:

Saccharomyces cerevisiae (strain atcc 204508 / s288c). Baker's yeast. Organism_taxid: 559292. Strain: atcc 204508 / s288c. Strain: atcc 204508 / s288c

Resolution:

2.80Å R-factor: 0.187 R-free: 0.206

Authors:

C.Dubiella,M.Groll

Key ref:

C.Dubiella et al. (2015). Selective Inhibition of the Immunoproteasome by Structure-Based Targeting of a Non-catalytic Cysteine. Angew Chem Int Ed Engl, 54, 15888-15891. PubMed id: 26563572 DOI: 10.1002/anie.201506631

Date:

09-Jul-15 Release date: 25-Nov-15

Protein chains

P23639  (PSA2_YEAST) -  Proteasome subunit alpha type-2 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 250 a.a.

Struc: 250 a.a.

Protein chains

P23638  (PSA3_YEAST) -  Proteasome subunit alpha type-3 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 258 a.a.

Struc: 244 a.a.

Protein chains

P40303  (PSA4_YEAST) -  Proteasome subunit alpha type-4 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 254 a.a.

Struc: 240 a.a.

Protein chains

P32379  (PSA5_YEAST) -  Proteasome subunit alpha type-5 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 260 a.a.

Struc: 235 a.a.

Protein chains

P40302  (PSA6_YEAST) -  Proteasome subunit alpha type-6 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 234 a.a.

Struc: 231 a.a.

Protein chains

P21242  (PSA7_YEAST) -  Probable proteasome subunit alpha type-7 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 288 a.a.

Struc: 243 a.a.

Protein chains

P21243  (PSA1_YEAST) -  Proteasome subunit alpha type-1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 252 a.a.

Struc: 241 a.a.

Protein chains

P25043  (PSB2_YEAST) -  Proteasome subunit beta type-2 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 261 a.a.

Struc: 222 a.a.

Protein chains

P25451  (PSB3_YEAST) -  Proteasome subunit beta type-3 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 205 a.a.

Struc: 204 a.a.

Protein chains

P22141  (PSB4_YEAST) -  Proteasome subunit beta type-4 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 198 a.a.

Struc: 195 a.a.

Protein chains

P30656  (PSB5_YEAST) -  Proteasome subunit beta type-5 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 287 a.a.

Struc: 212 a.a.*

Protein chains

P23724  (PSB6_YEAST) -  Proteasome subunit beta type-6 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 241 a.a.

Struc: 222 a.a.

Protein chains

P30657  (PSB7_YEAST) -  Proteasome subunit beta type-7 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 266 a.a.

Struc: 233 a.a.

Protein chains

P38624  (PSB1_YEAST) -  Proteasome subunit beta type-1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 215 a.a.

Struc: 196 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, a, b: E.C.3.4.25.1 - proteasome endopeptidase complex.
• Reaction: Cleavage at peptide bonds with very broad specificity.

DOI no: 10.1002/anie.201506631

Angew Chem Int Ed Engl 54:15888-15891 (2015)

PubMed id: 26563572

Selective Inhibition of the Immunoproteasome by Structure-Based Targeting of a Non-catalytic Cysteine.

C.Dubiella, R.Baur, H.Cui, E.M.Huber, M.Groll.

ABSTRACT

Clinically applied proteasome inhibitors induce cell death by concomitant blockage of constitutive and immunoproteasomes. In contrast, selective immunoproteasome inhibition is less cytotoxic and has the potential to modulate chronic inflammation and autoimmune diseases. In this study, we rationally designed decarboxylated peptides that covalently target a non-catalytic cysteine of the immunoproteasome subunit β5i with α-chloroacetamide-containing sidechains. The enhanced isoform specificity decreased cytotoxic effects and the compound suppressed the production of inflammatory cytokines. Structure-based optimization led to over 150-fold selectivity for subunit β5i over β5c. This new compound class provides a promising starting point for the development of selective immunoproteasome inhibitors as potential anti-inflammatory agents.