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PDBsum entry 4int

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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
4int
Jmol PyMol
Contents
Protein chains
250 a.a.
244 a.a.
241 a.a.
242 a.a.
233 a.a.
244 a.a.
243 a.a.
222 a.a.
204 a.a.
198 a.a.
212 a.a.
222 a.a.
233 a.a.
196 a.a.
Ligands
1G5 ×4
Waters ×1335
PDB id:
4int
Name: Hydrolase/hydrolase inhibitor
Title: Yeast 20s proteasome in complex with the vinyl sulfone lu122
Structure: Proteasome component y7. Chain: a, o. Synonym: macropain subunit y7, multicatalytic endopeptidase subunit y7, proteinase ysce subunit 7. Proteasome component y13. Chain: b, p. Synonym: macropain subunit y13, multicatalytic endopeptidas subunit y13, proteinase ysce subunit 13. Proteasome component pre6.
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Organism_taxid: 4932
Resolution:
2.90Å     R-factor:   0.222     R-free:   0.230
Authors: P.P.Geurink,W.A.Van Der Linden,A.C.Mirabella,N.Gallastegui,G Bruin,A.E.M.Blom,M.J.Voges,E.D.Mock,B.I.Florea,G.A.Van Der C.Driessen,M.Van Der Stelt,M.Groll,H.S.Overkleeft,A.F.Kisse
Key ref: P.P.Geurink et al. (2013). Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites. J Med Chem, 56, 1262-1275. PubMed id: 23320547 DOI: 10.1021/jm3016987
Date:
06-Jan-13     Release date:   30-Jan-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P23639  (PSA2_YEAST) -  Proteasome subunit alpha type-2
Seq:
Struc:
250 a.a.
250 a.a.
Protein chains
Pfam   ArchSchema ?
P23638  (PSA4_YEAST) -  Proteasome subunit alpha type-3
Seq:
Struc:
258 a.a.
244 a.a.
Protein chains
Pfam   ArchSchema ?
P40303  (PSA7_YEAST) -  Proteasome subunit alpha type-4
Seq:
Struc:
254 a.a.
241 a.a.
Protein chains
Pfam   ArchSchema ?
P32379  (PSA5_YEAST) -  Proteasome subunit alpha type-5
Seq:
Struc:
260 a.a.
242 a.a.
Protein chains
Pfam   ArchSchema ?
P40302  (PSA1_YEAST) -  Proteasome subunit alpha type-6
Seq:
Struc:
234 a.a.
233 a.a.
Protein chains
Pfam   ArchSchema ?
P21242  (PSA3_YEAST) -  Probable proteasome subunit alpha type-7
Seq:
Struc:
288 a.a.
244 a.a.
Protein chains
Pfam   ArchSchema ?
P21243  (PSA6_YEAST) -  Proteasome subunit alpha type-1
Seq:
Struc:
252 a.a.
243 a.a.
Protein chains
Pfam   ArchSchema ?
P25043  (PSB7_YEAST) -  Proteasome subunit beta type-2
Seq:
Struc:
261 a.a.
222 a.a.
Protein chains
Pfam   ArchSchema ?
P25451  (PSB3_YEAST) -  Proteasome subunit beta type-3
Seq:
Struc:
205 a.a.
204 a.a.
Protein chains
Pfam   ArchSchema ?
P22141  (PSB2_YEAST) -  Proteasome subunit beta type-4
Seq:
Struc:
198 a.a.
198 a.a.
Protein chains
Pfam   ArchSchema ?
P30656  (PSB5_YEAST) -  Proteasome subunit beta type-5
Seq:
Struc:
287 a.a.
212 a.a.
Protein chains
Pfam   ArchSchema ?
P23724  (PSB1_YEAST) -  Proteasome subunit beta type-6
Seq:
Struc:
241 a.a.
222 a.a.
Protein chains
Pfam   ArchSchema ?
P30657  (PSB4_YEAST) -  Proteasome subunit beta type-7
Seq:
Struc:
266 a.a.
233 a.a.
Protein chains
Pfam   ArchSchema ?
P38624  (PSB6_YEAST) -  Proteasome subunit beta type-1
Seq:
Struc:
215 a.a.
196 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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: E.C.3.4.25.1  - Proteasome endopeptidase complex.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage at peptide bonds with very broad specificity.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     plasma membrane   14 terms 
  Biological process     response to salt stress   10 terms 
  Biochemical function     molecular_function     8 terms  

 

 
DOI no: 10.1021/jm3016987 J Med Chem 56:1262-1275 (2013)
PubMed id: 23320547  
 
 
Incorporation of non-natural amino acids improves cell permeability and potency of specific inhibitors of proteasome trypsin-like sites.
P.P.Geurink, W.A.van der Linden, A.C.Mirabella, N.Gallastegui, G.de Bruin, A.E.Blom, M.J.Voges, E.D.Mock, B.I.Florea, G.A.van der Marel, C.Driessen, M.van der Stelt, M.Groll, H.S.Overkleeft, A.F.Kisselev.
 
  ABSTRACT  
 
Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that combinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antineoplastic activity than combinations currently used clinically.
 

 

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