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PDBsum entry 3gpj

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
3gpj
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
SY2 ×4
Waters ×1335
* Residue conservation analysis
PDB id:
3gpj
Name: Hydrolase
Title: Crystal structure of the yeast 20s proteasome in complex with syringolin 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. Fragment: sequence database residues 2-245. Synonym: macropain subunit y13, proteinase ysce subunit 13, multicatalytic endopeptidase complex subunit y13.
Source: Saccharomyces cerevisiae. Yeast. Organism_taxid: 4932. Organism_taxid: 4932
Resolution:
2.70Å     R-factor:   0.250     R-free:   0.264
Authors: M.Groll,R.Huber,M.Kaiser
Key ref:
J.Clerc et al. (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. PubMed id: 19359491 DOI: 10.1073/pnas.0901982106
Date:
23-Mar-09     Release date:   02-Jun-09    
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  

 

 
DOI no: 10.1073/pnas.0901982106 Proc Natl Acad Sci U S A 106:6507-6512 (2009)
PubMed id: 19359491  
 
 
Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition.
J.Clerc, M.Groll, D.J.Illich, A.S.Bachmann, R.Huber, B.Schellenberg, R.Dudler, M.Kaiser.
 
  ABSTRACT  
 
Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a K(i)' of 8.65 +/- 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics.
 
  Selected figure(s)  
 
Figure 1.
Structures of SylA (1), SylB (2), GlbA (3), and the lipophilic SylA derivative 21.
Figure 4.
X-ray analysis of the complex of SylB (2) and the 20S proteasome and comparison with other syrbactins. (A) Structure of syringolin A (1) and B (2). (B) Electrostatic potential surface [contoured from +15 kT/e (intense blue) to −15 kT/e (intense red)] of SylB covalently bound to β5. (C) Stereo representation of SylB (2) bound to the chymotryptic like active site in complex with 20S proteasome (rose, subunit β5; gray, subunit β6). (D) Structural superimposition of SylA (1, yellow), SylB (2, green), and GlbA (3, light gray).
 
  Figures were selected by an automated process.  

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.  
21226105 S.Osman, B.J.Albert, Y.Wang, M.Li, N.L.Czaicki, and K.Koide (2011).
Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464.
  Chemistry, 17, 895-904.  
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.  
21035730 H.J.Imker, D.Krahn, J.Clerc, M.Kaiser, and C.T.Walsh (2010).
N-acylation during glidobactin biosynthesis by the tridomain nonribosomal peptide synthetase module GlbF.
  Chem Biol, 17, 1077-1083.  
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.  
19863801 C.Ramel, M.Tobler, M.Meyer, L.Bigler, M.O.Ebert, B.Schellenberg, and R.Dudler (2009).
Biosynthesis of the proteasome inhibitor syringolin A: the ureido group joining two amino acids originates from bicarbonate.
  BMC Biochem, 10, 26.  
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.  
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.