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PDBsum entry 3d29

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
3d29
Jmol
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
FEB ×6
Waters ×1332
* Residue conservation analysis
PDB id:
3d29
Name: Hydrolase
Title: Proteasome inhibition by fellutamide b
Structure: Proteasome component y7. Chain: a, o. Synonym: macropain subunit y7, proteinase ysce subunit 7, multicatalytic endopeptidase complex subunit y7. Proteasome component y13. Chain: b, p. Synonym: macropain subunit y13, proteinase ysce subunit 13, multicatalytic endopeptidase complex subunit y13. Proteasome component pre6.
Source: Saccharomyces cerevisiae. Yeast. Organism_taxid: 4932. Strain: bakers yeast. Other_details: native purification from cell lysate. Other_details: native purification from cell lysate
Resolution:
2.60Å     R-factor:   0.240     R-free:   0.266
Authors: M.Groll,J.Hines,M.Fahnestock,M.C.Crews
Key ref: J.Hines et al. (2008). Proteasome inhibition by fellutamide B induces nerve growth factor synthesis. Chem Biol, 15, 501-512. PubMed id: 18482702
Date:
07-May-08     Release date:   10-Jun-08    
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, 1, 2: 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     nuclear outer membrane-endoplasmic reticulum membrane network   10 terms 
  Biological process     proteolysis   7 terms 
  Biochemical function     molecular_function     7 terms  

 

 
Chem Biol 15:501-512 (2008)
PubMed id: 18482702  
 
 
Proteasome inhibition by fellutamide B induces nerve growth factor synthesis.
J.Hines, M.Groll, M.Fahnestock, C.M.Crews.
 
  ABSTRACT  
 
Neurotrophic small molecules have the potential to aid in the treatment of neuronal injury and neurodegenerative diseases. The natural product fellutamide B, originally isolated from Penicillium fellutanum, potently induces nerve growth factor (NGF) release from fibroblasts and glial-derived cells, although the mechanism for this neurotrophic activity has not been elucidated. Here, we report that fellutamide B potently inhibits proteasome catalytic activity. High-resolution structural information obtained from cocrystallization of the 20S proteasome reveals novel aspects regarding beta-subunit binding and adduct formation by fellutamide B to inhibit their hydrolytic activity. We demonstrate that fellutamide B and other proteasome inhibitors increased NGF gene transcription via a cis-acting element (or elements) in the promoter. These results demonstrate an unrecognized connection between proteasome inhibition and NGF production, suggesting a possible new strategy in the development of neurotrophic agents.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20830349 J.Clerc, N.Li, D.Krahn, M.Groll, A.S.Bachmann, B.I.Florea, H.S.Overkleeft, and M.Kaiser (2011).
The natural product hybrid of Syringolin A and Glidobactin A synergizes proteasome inhibition potency with subsite selectivity.
  Chem Commun (Camb), 47, 385-387.  
20927454 P.M.Joyner, and R.H.Cichewicz (2011).
Bringing natural products into the fold - exploring the therapeutic lead potential of secondary metabolites for the treatment of protein-misfolding-related neurodegenerative diseases.
  Nat Prod Rep, 28, 26-47.  
21338914 T.Roemer, D.Xu, S.B.Singh, C.A.Parish, G.Harris, H.Wang, J.E.Davies, and G.F.Bills (2011).
Confronting the challenges of natural product-based antifungal discovery.
  Chem Biol, 18, 148-164.  
20814885 A.Baldisserotto, C.Franceschini, F.Scalambra, C.Trapella, M.Marastoni, F.Sforza, R.Gavioli, and R.Tomatis (2010).
Synthesis and proteasome inhibition of N-allyl vinyl ester-based peptides.
  J Pept Sci, 16, 659-663.  
20422068 J.J.La Clair (2010).
Natural product mode of action (MOA) studies: a link between natural and synthetic worlds.
  Nat Prod Rep, 27, 969-995.  
20981375 P.P.Geurink, B.I.Florea, G.A.Van der Marel, B.M.Kessler, and H.S.Overkleeft (2010).
Probing the proteasome cavity in three steps: bio-orthogonal photo-reactive suicide substrates.
  Chem Commun (Camb), 46, 9052-9054.  
19746508 J.Clerc, B.I.Florea, M.Kraus, M.Groll, R.Huber, A.S.Bachmann, R.Dudler, C.Driessen, H.S.Overkleeft, and M.Kaiser (2009).
Syringolin A selectively labels the 20 S proteasome in murine EL4 and wild-type and bortezomib-adapted leukaemic cell lines.
  Chembiochem, 10, 2638-2643.  
19359491 J.Clerc, M.Groll, D.J.Illich, A.S.Bachmann, R.Huber, B.Schellenberg, R.Dudler, and M.Kaiser (2009).
Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition.
  Proc Natl Acad Sci U S A, 106, 6507-6512.
PDB code: 3gpj
19706171 K.Lakomek, A.Dickmanns, M.Kettwig, H.Urlaub, R.Ficner, and T.Lübke (2009).
Initial insight into the function of the lysosomal 66.3 kDa protein from mouse by means of X-ray crystallography.
  BMC Struct Biol, 9, 56.
PDB codes: 3fgr 3fgt 3fgw
19109822 M.Groll, R.Huber, and L.Moroder (2009).
The persisting challenge of selective and specific proteasome inhibition.
  J Pept Sci, 15, 58-66.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.