PDBsum entry 4no8

Hydrolase/hydrolase inhibitor

PDB id: 4no8

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

2LV ×2

Metals

_MG ×8

Waters ×488

PDB id:

4no8

Name:

Hydrolase/hydrolase inhibitor

Title:

Ycp in complex with z-leu-leu-leu-ketoamide

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:

2.70Å R-factor: 0.194 R-free: 0.217

Authors:

M.L.Stein,H.Cui,P.Beck,C.Dubiella,C.Voss,A.Krueger,B.Schmidt,M.Groll

Key ref:

M.L.Stein et al. (2014). Systematic comparison of peptidic proteasome inhibitors highlights the α-ketoamide electrophile as an auspicious reversible lead motif. Angew Chem Int Ed Engl, 53, 1679-1683. PubMed id: 24403024 DOI: 10.1002/anie.201308984

Date:

19-Nov-13 Release date: 12-Feb-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: 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.

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.201308984

Angew Chem Int Ed Engl 53:1679-1683 (2014)

PubMed id: 24403024

Systematic comparison of peptidic proteasome inhibitors highlights the α-ketoamide electrophile as an auspicious reversible lead motif.

M.L.Stein, H.Cui, P.Beck, C.Dubiella, C.Voss, A.Krüger, B.Schmidt, M.Groll.

ABSTRACT

The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophilic C-terminus by which they react with the active proteolytic sites. Although the peptide moiety has attracted much attention in terms of subunit selectivity, the target specificity and biological stability of the compounds are largely determined by the reactive warheads. In this study, we have carried out a systematic investigation of described electrophiles by a combination of in vitro, in vivo, and structural methods in order to disclose the implications of altered functionality and chemical reactivity. Thereby, we were able to introduce and characterize the class of α-ketoamides as the most potent reversible inhibitors with possible applications for the therapy of solid tumors as well as autoimmune disorders.