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PDBsum entry 1jd2
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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1jd2

 

 

 

 

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JSmol 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
1QQ-TYR-ASN-R4K-
AKK ×2
Metals
_MG ×10
Waters ×2893
* Residue conservation analysis
PDB id:
1jd2
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of the yeast 20s proteasome:tmc-95a complex: a non- covalent proteasome inhibitor
Structure: Proteasome component y7. Chain: a, v. Synonym: macropain subunit y7, proteinase ysce subunit 7, multicatalytic endopeptidase complex subunit y7. Other_details: part of 20s subunit. Proteasome component y13. Chain: b, w. Synonym: macropain subunit y13, proteinase ysce subunit 13, multicatalytic endopeptidase complex subunit y13.
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Variant: sub61. Apiospora montagnei. Organism_taxid: 255776
Biol. unit: 28mer (from PQS)
Resolution:
3.00Å     R-factor:   0.251     R-free:   0.336
Authors: M.Groll,Y.Koguchi,R.Huber,J.Kohno
Key ref:
M.Groll et al. (2001). Crystal structure of the 20 S proteasome:TMC-95A complex: a non-covalent proteasome inhibitor. J Mol Biol, 311, 543-548. PubMed id: 11493007 DOI: 10.1006/jmbi.2001.4869
Date:
12-Jun-01     Release date:   13-Feb-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P23639  (PSA2_YEAST) -  Proteasome subunit alpha type-2 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		250 a.a.
250 a.a.
Protein chains
Pfam   ArchSchema ?
P23638  (PSA3_YEAST) -  Proteasome subunit alpha type-3 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		258 a.a.
244 a.a.
Protein chains
Pfam   ArchSchema ?
P40303  (PSA4_YEAST) -  Proteasome subunit alpha type-4 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		254 a.a.
241 a.a.
Protein chains
Pfam   ArchSchema ?
P32379  (PSA5_YEAST) -  Proteasome subunit alpha type-5 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		260 a.a.
242 a.a.
Protein chains
Pfam   ArchSchema ?
P40302  (PSA6_YEAST) -  Proteasome subunit alpha type-6 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		234 a.a.
233 a.a.
Protein chains
Pfam   ArchSchema ?
P21242  (PSA7_YEAST) -  Probable proteasome subunit alpha type-7 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		288 a.a.
244 a.a.
Protein chains
Pfam   ArchSchema ?
P21243  (PSA1_YEAST) -  Proteasome subunit alpha type-1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		252 a.a.
243 a.a.
Protein chains
Pfam   ArchSchema ?
P25043  (PSB2_YEAST) -  Proteasome subunit beta type-2 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		261 a.a.
222 a.a.
Protein chains
Pfam   ArchSchema ?
P25451  (PSB3_YEAST) -  Proteasome subunit beta type-3 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		205 a.a.
204 a.a.
Protein chains
Pfam   ArchSchema ?
P22141  (PSB4_YEAST) -  Proteasome subunit beta type-4 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		198 a.a.
198 a.a.
Protein chains
Pfam   ArchSchema ?
P30656  (PSB5_YEAST) -  Proteasome subunit beta type-5 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		287 a.a.
212 a.a.
Protein chains
Pfam   ArchSchema ?
P23724  (PSB6_YEAST) -  Proteasome subunit beta type-6 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		241 a.a.
222 a.a.
Protein chains
Pfam   ArchSchema ?
P30657  (PSB7_YEAST) -  Proteasome subunit beta type-7 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		266 a.a.
233 a.a.
Protein chains
Pfam   ArchSchema ?
P38624  (PSB1_YEAST) -  Proteasome subunit beta type-1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Seq:
Struc: 		215 a.a.
196 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: Chains A, B, C, D, E, F, G, I, J, L, M, P, Q, S, T, V, W, X, Y, Z, 1, 2: E.C.3.4.99.46  - Transferred entry: 3.4.25.1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 3: Chains H, K, N, O, R, U: E.C.3.4.25.1  - proteasome endopeptidase complex.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage at peptide bonds with very broad specificity.
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

 

 
DOI no: 10.1006/jmbi.2001.4869 J Mol Biol 311:543-548 (2001)
PubMed id: 11493007  
 
 
Crystal structure of the 20 S proteasome:TMC-95A complex: a non-covalent proteasome inhibitor.
M.Groll, Y.Koguchi, R.Huber, J.Kohno.
 
  ABSTRACT  
 
The 20 S proteasome core particle (CP), a multicatalytic protease, is involved in a variety of biologically important processes, including immune response, cell-cycle control, metabolic adaptation, stress response and cell differentiation. Therefore, selective inhibition of the CP will be one possible way to influence these essential pathways. Recently, a new class of specific proteasome inhibitors, TMC-95s, was investigated and we now present a biochemical and crystallographic characterisation of the yeast proteasome core particle in complex with the natural product TMC-95A. This unusual heterocyclic compound specifically blocks the active sites of CPs non-covalently, without modifying the nucleophilic Thr1 residue. The inhibitor is bound to the CP by specific hydrogen bonds with the main-chain atoms of the protein. Analysis of the crystal structure of the complex has revealed which portions of TMC-95s are essential for binding to the proteasome. This will form the basis for the development of synthetic selective proteasome inhibitors as promising candidates for anti-tumoral or anti-inflammatory drugs.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. (a) Chemical structure of TMC-95s including diastereomers A to D. (b) The lead structure segment of TMC-95s which contributes the most to proteasome inhibition. The S1 and S3 residues, shown in blue, mark specific amino acid residues that are major determinants for differential binding to proteasomal subunits. 		Figure 4.
Figure 4. Stereoview of the superimposition of TMC-95A and epoxomicin (including the Thr1 as a morpholino-ring adduct), with respect to subunit b2. TMC-95A is shown in yellow, epoxomicin is drawn in green and the active site Thr1 in black. The superimposition clearly indicates that the S1 and S3 pockets are occupied in a unique way by the corresponding residues of the inhibitors (blue ellipsoids).
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2001, 311, 543-548) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21104764 S.H.Shim (2011).
20S proteasome inhibitory activity of flavonoids isolated from Spatholobus suberectus.
  Phytother Res, 25, 615-618.  
20632995 C.Blackburn, K.M.Gigstad, P.Hales, K.Garcia, M.Jones, F.J.Bruzzese, C.Barrett, J.X.Liu, T.A.Soucy, D.S.Sappal, N.Bump, E.J.Olhava, P.Fleming, L.R.Dick, C.Tsu, M.D.Sintchak, and J.L.Blank (2010).
Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit.
  Biochem J, 430, 461-476.
PDB codes: 3mg0 3mg4 3mg6 3mg7 3mg8
20715286 M.Groll, N.Gallastegui, X.Maréchal, V.Le Ravalec, N.Basse, N.Richy, E.Genin, R.Huber, L.Moroder, J.Vidal, and M.Reboud-Ravaux (2010).
20S proteasome inhibition: designing noncovalent linear peptide mimics of the natural product TMC-95A.
  ChemMedChem, 5, 1701-1705.
PDB codes: 3nzj 3nzw 3nzx
  19471122 A.Kazi, H.Lawrence, W.C.Guida, M.L.McLaughlin, G.M.Springett, N.Berndt, R.M.Yip, and S.M.Sebti (2009).
Discovery of a novel proteasome inhibitor selective for cancer cells over non-transformed cells.
  Cell Cycle, 8, 1940-1951.  
19109822 M.Groll, R.Huber, and L.Moroder (2009).
The persisting challenge of selective and specific proteasome inhibition.
  J Pept Sci, 15, 58-66.  
18219406 M.Pucheault (2008).
Natural products: chemical instruments to apprehend biological symphony.
  Org Biomol Chem, 6, 424-432.  
17880010 S.Meiners, A.Ludwig, V.Stangl, and K.Stangl (2008).
Proteasome inhibitors: poisons and remedies.
  Med Res Rev, 28, 309-327.  
17696779 L.Borissenko, and M.Groll (2007).
Diversity of proteasomal missions: fine tuning of the immune response.
  Biol Chem, 388, 947-955.  
17390294 O.Drews, C.Zong, and P.Ping (2007).
Exploring proteasome complexes by proteomic approaches.
  Proteomics, 7, 1047-1058.  
16819628 C.Camps, V.Iranzo, R.M.Bremnes, and R.Sirera (2006).
Anorexia-Cachexia syndrome in cancer: implications of the ubiquitin-proteasome pathway.
  Support Care Cancer, 14, 1173-1183.  
17001679 Q.P.Dou (2006).
Lessons learned from Art Pardee in cell cycle, science, and life.
  J Cell Physiol, 209, 663-669.  
  16044664 M.Di Napoli, and B.McLaughlin (2005).
The ubiquitin-proteasome system as a drug target in cerebrovascular disease: therapeutic potential of proteasome inhibitors.
  Curr Opin Investig Drugs, 6, 686-699.  
15678420 M.Groll, M.Bochtler, H.Brandstetter, T.Clausen, and R.Huber (2005).
Molecular machines for protein degradation.
  Chembiochem, 6, 222-256.  
15163792 B.K.Albrecht, and R.M.Williams (2004).
A concise, total synthesis of the TMC-95A/B proteasome inhibitors.
  Proc Natl Acad Sci U S A, 101, 11949-11954.  
14705024 D.M.Smith, K.G.Daniel, Z.Wang, W.C.Guida, T.H.Chan, and Q.P.Dou (2004).
Docking studies and model development of tea polyphenol proteasome inhibitors: applications to rational drug design.
  Proteins, 54, 58-70.  
15368577 M.Kaiser, M.Groll, C.Siciliano, I.Assfalg-Machleidt, E.Weyher, J.Kohno, A.G.Milbradt, C.Renner, R.Huber, and L.Moroder (2004).
Binding mode of TMC-95A analogues to eukaryotic 20S proteasome.
  Chembiochem, 5, 1256-1266.  
15149232 S.Lin, Z.Q.Yang, B.H.Kwok, M.Koldobskiy, C.M.Crews, and S.J.Danishefsky (2004).
Total synthesis of TMC-95A and -B via a new reaction leading to Z-enamides. Some preliminary findings as to SAR.
  J Am Chem Soc, 126, 6347-6355.  
12782679 I.R.Garrett, D.Chen, G.Gutierrez, M.Zhao, A.Escobedo, G.Rossini, S.E.Harris, W.Gallwitz, K.B.Kim, S.Hu, C.M.Crews, and G.R.Mundy (2003).
Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro.
  J Clin Invest, 111, 1771-1782.  
12861018 J.Lundgren, P.Masson, C.A.Realini, and P.Young (2003).
Use of RNA interference and complementation to study the function of the Drosophila and human 26S proteasome subunit S13.
  Mol Cell Biol, 23, 5320-5330.  
14675543 M.Groll, and T.Clausen (2003).
Molecular shredders: how proteasomes fulfill their role.
  Curr Opin Struct Biol, 13, 665-673.  
12794861 Z.Q.Yang, B.H.Kwok, S.Lin, M.A.Koldobskiy, C.M.Crews, and S.J.Danishefsky (2003).
Simplified synthetic TMC-95A/B analogues retain the potency of proteasome inhibitory activity.
  Chembiochem, 4, 508-513.  
12409653 J.Adams (2002).
Proteasome inhibitors as new anticancer drugs.
  Curr Opin Oncol, 14, 628-634.  
12491396 S.Lin, and S.J.Danishefsky (2002).
The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: discovery of a new method to generate cis-propenyl amides.
  Angew Chem Int Ed Engl, 41, 512-515.  
11514224 A.F.Kisselev, and A.L.Goldberg (2001).
Proteasome inhibitors: from research tools to drug candidates.
  Chem Biol, 8, 739-758.  
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 codes are shown on the right.

 

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