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PDBsum entry 2f16
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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
2f16

 

 

 

 

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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
BO2 ×6
Waters ×1037
* Residue conservation analysis
PDB id:
2f16
Name: Hydrolase
Title: Crystal structure of the yeast 20s proteasome in complex with bortezomib
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. Baker's yeast. Organism_taxid: 4932. Organism_taxid: 4932
Biol. unit: 28mer (from PQS)
Resolution:
2.80Å     R-factor:   0.231     R-free:   0.264
Authors: M.Groll
Key ref:
M.Groll et al. (2006). Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure, 14, 451-456. PubMed id: 16531229 DOI: 10.1016/j.str.2005.11.019
Date:
14-Nov-05     Release date:   21-Mar-06    
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: 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.

 

 
DOI no: 10.1016/j.str.2005.11.019 Structure 14:451-456 (2006)
PubMed id: 16531229  
 
 
Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome.
M.Groll, C.R.Berkers, H.L.Ploegh, H.Ovaa.
 
  ABSTRACT  
 
The dipeptide boronic acid bortezomib, also termed VELCADE, is a proteasome inhibitor now in use for the treatment of multiple myeloma, and its use for the treatment of other malignancies is being explored. We determined the crystal structure of the yeast 20S proteasome in complex with bortezomib to establish the specificity and binding mode of bortezomib to the proteasome's different catalytically active sites. This structure should enable the rational design of new boronic acid derivatives with improved affinities and specificities for individual active subunits.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Critical Interactions of Bortezomib with Active Site Residues Responsible for Chymotryptic and Caspase-like Activities
Schematic overview of bortezomib bound to (A) the chymotryptic-like active site and (B) the caspase-like active site. Hydrogen bonds with correlated distances in Å are shown as brown dashed lines, whereas characteristic oxygen and nitrogen atoms are presented in red and blue capitals. The amino acid, which is responsible for the character and binding mode to the P3-pyrazine-2-carboxyl side chain of the inhibitor is located at the adjacent b-type subunit and shown in gray. The defined water molecule forming tight hydrogen bonds to the protein is depicted in magenta, and the inhibitor is shown in green.
 
  The above figure is reprinted by permission from Cell Press: Structure (2006, 14, 451-456) copyright 2006.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
20360563 H.M.Albers, A.Dong, L.A.van Meeteren, D.A.Egan, M.Sunkara, E.W.van Tilburg, K.Schuurman, O.van Tellingen, A.J.Morris, S.S.Smyth, W.H.Moolenaar, and H.Ovaa (2010).
Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation.
  Proc Natl Acad Sci U S A, 107, 7257-7262.  
20461747 H.S.Ban, H.Minegishi, K.Shimizu, M.Maruyama, Y.Yasui, and H.Nakamura (2010).
Discovery of carboranes as inducers of 20S proteasome activity.
  ChemMedChem, 5, 1236-1241.  
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
20555361 M.Ri, S.Iida, T.Nakashima, H.Miyazaki, F.Mori, A.Ito, A.Inagaki, S.Kusumoto, T.Ishida, H.Komatsu, Y.Shiotsu, and R.Ueda (2010).
Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress.
  Leukemia, 24, 1506-1512.  
  19291708 S.Jin, Y.Cheng, S.Reid, M.Li, and B.Wang (2010).
Carbohydrate recognition by boronolectins, small molecules, and lectins.
  Med Res Rev, 30, 171-257.  
  20927786 T.A.Gulder, and B.S.Moore (2010).
Salinosporamide natural products: potent 20 s proteasome inhibitors as promising cancer chemotherapeutics.
  Angew Chem Int Ed Engl, 49, 9346-9367.  
  19960052 A.Bolognese, A.Esposito, M.Manfra, L.Catalano, F.Petruzziello, M.C.Martorelli, R.Pagliuca, V.Mazzarelli, M.Ottiero, M.Scalfaro, and B.Rotoli (2009).
An NMR Study of the Bortezomib Degradation under Clinical Use Conditions.
  Adv Hematol, 2009, 704928.  
  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.  
19812037 A.Navon, and A.Ciechanover (2009).
The 26 S proteasome: from basic mechanisms to drug targeting.
  J Biol Chem, 284, 33713-33718.  
19190249 E.B.Golden, P.Y.Lam, A.Kardosh, K.J.Gaffney, E.Cadenas, S.G.Louie, N.A.Petasis, T.C.Chen, and A.H.Schönthal (2009).
Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.
  Blood, 113, 5927-5937.  
19968303 H.J.Imker, C.T.Walsh, and W.M.Wuest (2009).
SylC catalyzes ureido-bond formation during biosynthesis of the proteasome inhibitor syringolin A.
  J Am Chem Soc, 131, 18263-18265.  
19830290 H.S.Ban, T.Usui, W.Nabeyama, H.Morita, K.Fukuzawa, and H.Nakamura (2009).
Discovery of boron-conjugated 4-anilinoquinazoline as a prolonged inhibitor of EGFR tyrosine kinase.
  Org Biomol Chem, 7, 4415-4427.  
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.  
19821999 J.K.Agyin, B.Santhamma, H.B.Nair, S.S.Roy, and R.R.Tekmal (2009).
BU-32: a novel proteasome inhibitor for breast cancer.
  Breast Cancer Res, 11, R74.  
19109822 M.Groll, R.Huber, and L.Moroder (2009).
The persisting challenge of selective and specific proteasome inhibition.
  J Pept Sci, 15, 58-66.  
19021159 M.Orzáez, A.Gortat, L.Mondragón, and E.Pérez-Payá (2009).
Peptides and peptide mimics as modulators of apoptotic pathways.
  ChemMedChem, 4, 146-160.  
19679091 P.A.Osmulski, M.Hochstrasser, and M.Gaczynska (2009).
A tetrahedral transition state at the active sites of the 20S proteasome is coupled to opening of the alpha-ring channel.
  Structure, 17, 1137-1147.  
19559507 S.S.Hindo, M.Frezza, D.Tomco, M.J.Heeg, L.Hryhorczuk, B.R.McGarvey, Q.P.Dou, and C.N.Verani (2009).
Metals in anticancer therapy: copper(II) complexes as inhibitors of the 20S proteasome.
  Eur J Med Chem, 44, 4353-4361.  
18754030 X.Mao, X.Li, R.Sprangers, X.Wang, A.Venugopal, T.Wood, Y.Zhang, D.A.Kuntz, E.Coe, S.Trudel, D.Rose, R.A.Batey, L.E.Kay, and A.D.Schimmer (2009).
Clioquinol inhibits the proteasome and displays preclinical activity in leukemia and myeloma.
  Leukemia, 23, 585-590.  
18823992 A.Anbanandam, D.C.Albarado, D.C.Tirziu, M.Simons, and S.Veeraraghavan (2008).
Molecular basis for proline- and arginine-rich peptide inhibition of proteasome.
  J Mol Biol, 384, 219-227.  
18928262 M.Groll, E.P.Balskus, and E.N.Jacobsen (2008).
Structural analysis of spiro beta-lactone proteasome inhibitors.
  J Am Chem Soc, 130, 14981-14983.
PDB codes: 3dy3 3dy4
18565852 R.Oerlemans, N.E.Franke, Y.G.Assaraf, J.Cloos, I.van Zantwijk, C.R.Berkers, G.L.Scheffer, K.Debipersad, K.Vojtekova, C.Lemos, J.W.van der Heijden, B.Ylstra, G.J.Peters, G.L.Kaspers, B.A.Dijkmans, R.J.Scheper, and G.Jansen (2008).
Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein.
  Blood, 112, 2489-2499.  
18026118 M.F.Kleijnen, J.Roelofs, S.Park, N.A.Hathaway, M.Glickman, R.W.King, and D.Finley (2007).
Stability of the proteasome can be regulated allosterically through engagement of its proteolytic active sites.
  Nat Struct Mol Biol, 14, 1180-1188.  
18047741 P.G.Corn (2007).
Role of the ubiquitin proteasome system in renal cell carcinoma.
  BMC Biochem, 8, S4.  
17592829 Y.A.Elnakady, M.Rohde, F.Sasse, C.Backes, A.Keller, H.P.Lenhof, K.J.Weissman, and R.Müller (2007).
Evidence for the mode of action of the highly cytotoxic Streptomyces polyketide kendomycin.
  Chembiochem, 8, 1261-1272.  
17112720 P.R.Mittl, and M.G.Grütter (2006).
Opportunities for structure-based design of protease-directed drugs.
  Curr Opin Struct Biol, 16, 769-775.  
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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