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PDBsum entry 3fzk
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protein ligands metals Protein-protein interface(s) links
Chaperone PDB id
3fzk

 

 

 

 

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Contents
Protein chains
377 a.a. *
111 a.a. *
Ligands
TRS
3BK
Metals
_CL
Waters ×277
* Residue conservation analysis
PDB id:
3fzk
Name: Chaperone
Title: Crystal structures of hsc70/bag1 in complex with small molecule inhibitors
Structure: Heat shock cognate 71 kda protein. Chain: a. Fragment: unp residues 4-381. Synonym: heat shock 70 kda protein 8. Engineered: yes. Bag family molecular chaperone regulator 1. Chain: b. Fragment: unp residues 222-334. Synonym: bag-1, bcl-2-associated athanogene 1, glucocorticoid
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hspa8, hsc70, hsp73, hspa10. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: bag1, hap.
Resolution:
2.10Å     R-factor:   0.222     R-free:   0.294
Authors: P.Dokurno,D.S.Williamson,J.B.Murray,A.E.Surgenor
Key ref: D.S.Williamson et al. (2009). Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem, 52, 1510-1513. PubMed id: 19256508
Date:
26-Jan-09     Release date:   17-Mar-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P11142  (HSP7C_HUMAN) -  Heat shock cognate 71 kDa protein from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		646 a.a.
377 a.a.
Protein chain
Pfam   ArchSchema ?
Q99933  (BAG1_HUMAN) -  BAG family molecular chaperone regulator 1 from Homo sapiens
Seq:
Struc: 		345 a.a.
111 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain A: E.C.3.6.4.10  - non-chaperonin molecular chaperone ATPase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + H2O = ADP + phosphate + H+
ATP
 + H2O
 =
ADP
Bound ligand (Het Group name = 3BK)
matches with 51.35% similarity 		+ phosphate
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
J Med Chem 52:1510-1513 (2009)
PubMed id: 19256508  
 
 
Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design.
D.S.Williamson, J.Borgognoni, A.Clay, Z.Daniels, P.Dokurno, M.J.Drysdale, N.Foloppe, G.L.Francis, C.J.Graham, R.Howes, A.T.Macias, J.B.Murray, R.Parsons, T.Shaw, A.E.Surgenor, L.Terry, Y.Wang, M.Wood, A.J.Massey.
 
  ABSTRACT  
 
The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displayed potency against HCT116 cells. Exposure of compound 12 to HCT116 cells caused significant reduction in cellular levels of Raf-1 and Her2 at concentrations similar to that which caused cell growth arrest.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21426241 I.L.Cockburn, E.R.Pesce, J.M.Pryzborski, M.T.Davies-Coleman, P.G.Clark, R.A.Keyzers, L.L.Stephens, and G.L.Blatch (2011).
Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1.
  Biol Chem, 392, 431-438.  
20223214 A.Arakawa, N.Handa, N.Ohsawa, M.Shida, T.Kigawa, F.Hayashi, M.Shirouzu, and S.Yokoyama (2010).
The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange.
  Structure, 18, 309-319.
PDB codes: 1ugo 1uk5 2d9d 3a8y
20012863 A.J.Massey, D.S.Williamson, H.Browne, J.B.Murray, P.Dokurno, T.Shaw, A.T.Macias, Z.Daniels, S.Geoffroy, M.Dopson, P.Lavan, N.Matassova, G.L.Francis, C.J.Graham, R.Parsons, Y.Wang, A.Padfield, M.Comer, M.J.Drysdale, and M.Wood (2010).
A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells.
  Cancer Chemother Pharmacol, 66, 535-545.  
20348093 A.M.Wang, Y.Morishima, K.M.Clapp, H.M.Peng, W.B.Pratt, J.E.Gestwicki, Y.Osawa, and A.P.Lieberman (2010).
Inhibition of hsp70 by methylene blue affects signaling protein function and ubiquitination and modulates polyglutamine protein degradation.
  J Biol Chem, 285, 15714-15723.  
20345171 C.Bissantz, B.Kuhn, and M.Stahl (2010).
A medicinal chemist's guide to molecular interactions.
  J Med Chem, 53, 5061-5084.  
20717760 F.Boschelli, J.M.Golas, R.Petersen, V.Lau, L.Chen, D.Tkach, Q.Zhao, D.S.Fruhling, H.Liu, C.Nam, and K.T.Arndt (2010).
A cell-based screen for inhibitors of protein folding and degradation.
  Cell Stress Chaperones, 15, 913-927.  
19694756 J.Cellitti, Z.Zhang, S.Wang, B.Wu, H.Yuan, P.Hasegawa, D.G.Guiney, and M.Pellecchia (2009).
Small molecule DnaK modulators targeting the beta-domain.
  Chem Biol Drug Des, 74, 349-357.  
19860737 S.Patury, Y.Miyata, and J.E.Gestwicki (2009).
Pharmacological targeting of the Hsp70 chaperone.
  Curr Top Med Chem, 9, 1337-1351.  
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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