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

 

 

 

 

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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
SA1 ×6
Waters ×1017
* Residue conservation analysis
PDB id:
2fak
Name: Hydrolase
Title: Crystal structure of salinosporamide a in complex with the yeast 20s proteasome
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:   0.229     R-free:   0.254
Authors: M.Groll,B.C.Potts
Key ref: M.Groll et al. (2006). Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J Am Chem Soc, 128, 5136-5141. PubMed id: 16608349 DOI: 10.1021/ja058320b
Date:
07-Dec-05     Release date:   18-Apr-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: 10.1021/ja058320b J Am Chem Soc 128:5136-5141 (2006)
PubMed id: 16608349  
 
 
Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding.
M.Groll, R.Huber, B.C.Potts.
 
  ABSTRACT  
 
The crystal structures of the yeast 20S proteasome core particle (CP) in complex with Salinosporamides A (NPI-0052; 1) and B (4) were solved at <3 angstroms resolution. Each ligand is covalently bound to Thr1O(gamma) via an ester linkage to the carbonyl derived from the beta-lactone ring of the inhibitor. In the case of 1, nucleophilic addition to the beta-lactone ring is followed by addition of C-3O to the chloroethyl group, giving rise to a cyclic ether. The crystal structures were compared to that of the omuralide/CP structure solved previously, and the collective data provide new insights into the mechanism of inhibition and irreversible binding of 1. Upon opening of the beta-lactone ring, C-3O assumes the position occupied by a water molecule in the unligated enzyme and hinders deacylation of the enzyme-ligand complex. Furthermore, the resulting protonation state of Thr1NH2 deactivates the catalytic N-terminus.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21154492 A.S.Eustáquio, S.J.Nam, K.Penn, A.Lechner, M.C.Wilson, W.Fenical, P.R.Jensen, and B.S.Moore (2011).
The discovery of salinosporamide K from the Marine Bacterium "Salinispora pacifica" by genome mining gives insight into pathway evolution.
  Chembiochem, 12, 61-64.  
21387511 S.Rachid, L.Huo, J.Herrmann, M.Stadler, B.Köpcke, J.Bitzer, and R.Müller (2011).
Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors.
  Chembiochem, 12, 922-931.  
21058386 Y.Kaiya, J.Hasegawa, T.Momose, T.Sato, and N.Chida (2011).
Total synthesis of (-)-salinosporamide a.
  Chem Asian J, 6, 209-219.  
20457000 A.F.Kluge, and R.C.Petter (2010).
Acylating drugs: redesigning natural covalent inhibitors.
  Curr Opin Chem Biol, 14, 421-427.  
20479958 B.C.Potts, and K.S.Lam (2010).
Generating a generation of proteasome inhibitors: from microbial fermentation to total synthesis of salinosporamide a (marizomib) and other salinosporamides.
  Mar Drugs, 8, 835-880.  
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
20498903 H.Nguyen, G.Ma, and D.Romo (2010).
A(1,3)-strain enabled retention of chirality during bis-cyclization of beta-ketoamides: total synthesis of (-)-salinosporamide A and (-)-homosalinosporamide A.
  Chem Commun (Camb), 46, 4803-4805.  
20931575 J.C.Kwan, and H.Luesch (2010).
Weapons in disguise--activating mechanisms and protecting group chemistry in nature.
  Chemistry, 16, 13020-13029.  
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.  
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
  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.  
20505154 X.Li, T.E.Wood, R.Sprangers, G.Jansen, N.E.Franke, X.Mao, X.Wang, Y.Zhang, S.E.Verbrugge, H.Adomat, Z.H.Li, S.Trudel, C.Chen, T.L.Religa, N.Jamal, H.Messner, J.Cloos, D.R.Rose, A.Navon, E.Guns, R.A.Batey, L.E.Kay, and A.D.Schimmer (2010).
Effect of noncompetitive proteasome inhibition on bortezomib resistance.
  J Natl Cancer Inst, 102, 1069-1082.  
19590008 A.S.Eustáquio, R.P.McGlinchey, Y.Liu, C.Hazzard, L.L.Beer, G.Florova, M.M.Alhamadsheh, A.Lechner, A.J.Kale, Y.Kobayashi, K.A.Reynolds, and B.S.Moore (2009).
Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine.
  Proc Natl Acad Sci U S A, 106, 12295-12300.  
19182209 C.P.Miller, S.Rudra, M.J.Keating, W.G.Wierda, M.Palladino, and J.Chandra (2009).
Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells.
  Blood, 113, 4289-4299.  
19109822 M.Groll, R.Huber, and L.Moroder (2009).
The persisting challenge of selective and specific proteasome inhibition.
  J Pept Sci, 15, 58-66.  
19746976 M.Nett, T.A.Gulder, A.J.Kale, C.C.Hughes, and B.S.Moore (2009).
Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica.
  J Med Chem, 52, 6163-6167.  
19022511 P.G.Williams (2009).
Panning for chemical gold: marine bacteria as a source of new therapeutics.
  Trends Biotechnol, 27, 45-52.  
19440739 S.Zhang, Y.Shi, H.Jin, Z.Liu, L.Zhang, and L.Zhang (2009).
Covalent complexes of proteasome model with peptide aldehyde inhibitors MG132 and MG101: docking and molecular dynamics study.
  J Mol Model, 15, 1481-1490.  
19481972 T.A.Gulder, and B.S.Moore (2009).
Chasing the treasures of the sea - bacterial marine natural products.
  Curr Opin Microbiol, 12, 252-260.  
19022674 W.Fenical, P.R.Jensen, M.A.Palladino, K.S.Lam, G.K.Lloyd, and B.C.Potts (2009).
Discovery and development of the anticancer agent salinosporamide A (NPI-0052).
  Bioorg Med Chem, 17, 2175-2180.  
19374124 Y.A.Chan, A.M.Podevels, B.M.Kevany, and M.G.Thomas (2009).
Biosynthesis of polyketide synthase extender units.
  Nat Prod Rep, 26, 90.  
18291314 C.S.Neumann, D.G.Fujimori, and C.T.Walsh (2008).
Halogenation strategies in natural product biosynthesis.
  Chem Biol, 15, 99.  
19007431 D.Chauhan, G.Bianchi, and K.C.Anderson (2008).
Targeting the UPS as therapy in multiple myeloma.
  BMC Biochem, 9, S1.  
18239916 G.Tsueng, and K.S.Lam (2008).
A low-sodium-salt formulation for the fermentation of salinosporamides by Salinispora tropica strain NPS21184.
  Appl Microbiol Biotechnol, 78, 821-826.  
18677472 G.Tsueng, and K.S.Lam (2008).
Growth of Salinispora tropica strains CNB440, CNB476, and NPS21184 in nonsaline, low-sodium media.
  Appl Microbiol Biotechnol, 80, 873-880.  
18239915 G.Tsueng, S.Teisan, and K.S.Lam (2008).
Defined salt formulations for the growth of Salinispora tropica strain NPS21184 and the production of salinosporamide A (NPI-0052) and related analogs.
  Appl Microbiol Biotechnol, 78, 827-832.  
18523554 J.Prudhomme, E.McDaniel, N.Ponts, S.Bertani, W.Fenical, P.Jensen, and K.Le Roch (2008).
Marine actinomycetes: a new source of compounds against the human malaria parasite.
  PLoS ONE, 3, e2335.  
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
18497896 M.S.Butler (2008).
Natural products to drugs: natural product-derived compounds in clinical trials.
  Nat Prod Rep, 25, 475-516.  
18512922 R.P.McGlinchey, M.Nett, A.S.Eustáquio, R.N.Asolkar, W.Fenical, and B.S.Moore (2008).
Engineered biosynthesis of antiprotealide and other unnatural salinosporamide proteasome inhibitors.
  J Am Chem Soc, 130, 7822-7823.  
17880010 S.Meiners, A.Ludwig, V.Stangl, and K.Stangl (2008).
Proteasome inhibitors: poisons and remedies.
  Med Res Rev, 28, 309-327.  
  19064254 Z.Huang, Y.Feng, D.Chen, X.Wu, S.Huang, X.Wang, X.Xiao, W.Li, N.Huang, L.Gu, G.Zhong, and J.Chai (2008).
Structural basis for activation and inhibition of the secreted chlamydia protease CPAF.
  Cell Host Microbe, 4, 529-542.
PDB codes: 3dja 3dor 3dpm 3dpn
17477539 G.Ma, H.Nguyen, and D.Romo (2007).
Concise total synthesis of (+/-)-salinosporamide A, (+/-)-cinnabaramide A, and derivatives via a bis-cyclization process: implications for a biosynthetic pathway?
  Org Lett, 9, 2143-2146.  
17340108 G.Tsueng, K.A.McArthur, B.C.Potts, and K.S.Lam (2007).
Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins.
  Appl Microbiol Biotechnol, 75, 999.  
17721007 G.Tsueng, and K.S.Lam (2007).
Stabilization effect of resin on the production of potent proteasome inhibitor NPI-0052 during submerged fermentation of Salinispora tropica.
  J Antibiot (Tokyo), 60, 469-472.  
17609425 K.S.Ahn, G.Sethi, T.H.Chao, S.T.Neuteboom, M.M.Chaturvedi, M.A.Palladino, A.Younes, and B.B.Aggarwal (2007).
Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products.
  Blood, 110, 2286-2295.  
17390584 K.S.Lam, G.Tsueng, K.A.McArthur, S.S.Mitchell, B.C.Potts, and J.Xu (2007).
Effects of halogens on the production of salinosporamides by the obligate marine actinomycete Salinispora tropica.
  J Antibiot (Tokyo), 60, 13-19.  
17696779 L.Borissenko, and M.Groll (2007).
Diversity of proteasomal missions: fine tuning of the immune response.
  Biol Chem, 388, 947-955.  
17441136 M.Shibasaki, M.Kanai, and N.Fukuda (2007).
Total synthesis of lactacystin and salinosporamide A.
  Chem Asian J, 2, 20-38.  
17554770 N.Denora, B.C.Potts, and V.J.Stella (2007).
A mechanistic and kinetic study of the beta-lactone hydrolysis of Salinosporamide A (NPI-0052), a novel proteasome inhibitor.
  J Pharm Sci, 96, 2037-2047.  
17047643 D.Chauhan, T.Hideshima, and K.C.Anderson (2006).
A novel proteasome inhibitor NPI-0052 as an anticancer therapy.
  Br J Cancer, 95, 961-965.  
17049224 F.E.Koehn (2006).
Therapeutic potential of natural product signal transduction agents.
  Curr Opin Biotechnol, 17, 631-637.  
17108984 W.Fenical, and P.R.Jensen (2006).
Developing a new resource for drug discovery: marine actinomycete bacteria.
  Nat Chem Biol, 2, 666-673.  
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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