PDBsum entry 4r18

Hydrolase/hydrolase inhibitor

PDB id: 4r18

Contents

Protein chains

250 a.a.

244 a.a.

240 a.a.

235 a.a.

231 a.a.

243 a.a.

241 a.a.

226 a.a.

204 a.a.

195 a.a.

211 a.a.

222 a.a.

233 a.a.

196 a.a.

Ligands

ABA ×2

Metals

_MG ×11

Waters ×1740

PDB id:

4r18

Name:

Hydrolase/hydrolase inhibitor

Title:

Ligand-induced lys33-thr1 crosslinking at subunit beta5 of the yeast 20s proteasome

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 s288c. Baker's yeast. Organism_taxid: 559292. Strain: atcc 204508 / s288c. Strain: atcc 204508 / s288c

Resolution:

2.40Å R-factor: 0.178 R-free: 0.195

Authors:

C.Dubiella,H.Cui,M.Gersch,A.J.Brouwer,S.A.Sieber,A.Krueger,R.Liskamp, M.Groll

Key ref:

C.Dubiella et al. (2014). Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site. Angew Chem Int Ed Engl, 53, 11969-11973. PubMed id: 25244435 DOI: 10.1002/anie.201406964

Date:

04-Aug-14 Release date: 15-Oct-14

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: 226 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: 211 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.

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.201406964

Angew Chem Int Ed Engl 53:11969-11973 (2014)

PubMed id: 25244435

Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site.

C.Dubiella, H.Cui, M.Gersch, A.J.Brouwer, S.A.Sieber, A.Krüger, R.M.Liskamp, M.Groll.

ABSTRACT

The concept of proteasome inhibition ranks among the latest achievements in the treatment of blood cancer and represents a promising strategy for modulating autoimmune diseases. In this study, we describe peptidic sulfonyl fluoride inhibitors that selectively block the catalytic β5 subunit of the immunoproteasome by inducing only marginal cytotoxic effects. Structural and mass spectrometric analyses revealed a novel reaction mechanism involving polarity inversion and irreversible crosslinking of the proteasomal active site. We thus identified the sulfonyl fluoride headgroup for the development and optimization of immunoproteasome selective compounds and their possible application in autoimmune disorders.