PDBsum entry 4eu2

Hydrolase/hydrolase inhibitor

PDB id: 4eu2

Contents

Protein chains

241 a.a.

249 a.a.

244 a.a.

241 a.a.

242 a.a.

232 a.a.

244 a.a.

196 a.a.

222 a.a.

204 a.a.

196 a.a.

212 a.a.

222 a.a.

233 a.a.

Ligands

WPI ×6

Waters ×1009

PDB id:

4eu2

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of 20s proteasome with novel inhibitor k-7174

Structure:

Proteasome component c7-alpha. Chain: a, o. Fragment: unp residues 10-250. Synonym: macropain subunit c7-alpha, multicatalytic endopeptidase complex c7, proteasome component y8, proteinase ysce subunit 7, scl1 suppressor protein. Proteasome component y7. Chain: b, p. Synonym: macropain subunit y7, multicatalytic endopeptidase complex

Source:

Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 559292. Strain: s288c. Strain: s288c

Resolution:

2.51Å R-factor: 0.205 R-free: 0.255

Authors:

J.Kikuchi,N.Shibayama,S.Yamada,T.Wada,M.Nobuyoshi,T.Izumi,M.Akutsu, Y.Kano,M.Ohki,K.Sugiyama,S.-Y.Park,Y.Furukawa

Key ref:

J.Kikuchi et al. (2013). Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding. Plos One, 8, e60649. PubMed id: 23593271 DOI: 10.1371/journal.pone.0060649

Date:

25-Apr-12 Release date: 01-May-13

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

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

Seq: 250 a.a.

Struc: 249 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: 241 a.a.

Protein chains

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

Seq: 260 a.a.

Struc: 242 a.a.

Protein chains

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

Seq: 234 a.a.

Struc: 232 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: 244 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.

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: 196 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.

* 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, 1, 2: E.C.3.4.25.1 - proteasome endopeptidase complex.
• Reaction: Cleavage at peptide bonds with very broad specificity.

DOI no: 10.1371/journal.pone.0060649

Plos One 8:e60649 (2013)

PubMed id: 23593271

Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.

J.Kikuchi, N.Shibayama, S.Yamada, T.Wada, M.Nobuyoshi, T.Izumi, M.Akutsu, Y.Kano, K.Sugiyama, M.Ohki, S.Y.Park, Y.Furukawa.

ABSTRACT

The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.