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PDBsum entry 1osf
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protein ligands links
Cell cycle PDB id
1osf

 

 

 

 

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Contents
Protein chain
215 a.a. *
Ligands
KOS
MPD ×2
ACY ×2
Waters ×277
* Residue conservation analysis
PDB id:
1osf
Name: Cell cycle
Title: Human hsp90 in complex with 17-desmethoxy-17-n,n- dimethylaminoethylamino-geldanamycin
Structure: Heat shock 90kda protein 1, alpha. Heat shock 90kd protein 1, alpha. Chain: a. Fragment: residues 9-223. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.75Å     R-factor:   0.184     R-free:   0.219
Authors: J.M.Jez,J.C.-H.Chen,G.Rastelli,R.M.Stroud,D.V.Santi
Key ref:
J.M.Jez et al. (2003). Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem Biol, 10, 361-368. PubMed id: 12725864 DOI: 10.1016/S1074-5521(03)00075-9
Date:
19-Mar-03     Release date:   27-May-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P07900  (HS90A_HUMAN) -  Heat shock protein HSP 90-alpha from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		732 a.a.
215 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.6.4.10  - non-chaperonin molecular chaperone ATPase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + H2O = ADP + phosphate + H+
ATP
 + H2O
 = ADP
 + phosphate
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1016/S1074-5521(03)00075-9 Chem Biol 10:361-368 (2003)
PubMed id: 12725864  
 
 
Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90.
J.M.Jez, J.C.Chen, G.Rastelli, R.M.Stroud, D.V.Santi.
 
  ABSTRACT  
 
Hsp90 is an attractive chemotherapeutic target because it chaperones the folding of proteins found in multiple signal transduction pathways. We describe the 1.75 A resolution crystal structure of human Hsp90 alpha (residues 9-236) complexed with 17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin (17-DMAG). The structure revealed an altered set of interactions between the 17-substituent and the protein compared to geldanamycin and the 17-dimethylaminoethyl moiety pointing into solvent, but otherwise was similar to that reported for the complex with geldanamycin. Targeted molecular dynamics simulations and energetic analysis indicate that geldanamycin undergoes two major conformational changes when it binds Hsp90, with the key step of the conversion being the trans to cis conformational change of the macrocycle amide bond. We speculate that 17-DMAG analogs constrained to a cis-amide in the ground state could provide a significant increase in affinity for Hsp90.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. Interactions between 17-DMAG and Hsp90Schematic drawing of interactions between 17-DMAG and the ATP binding site of human Hsp90α. Hydrogen bonds are shown as dotted lines with distances given in angstroms. 		Figure 5.
Figure 5. Molecular Dynamics of the Conformational Change of GeldanamycinSuperimposition of averaged structures collected during the 800 ps TMD simulation that converts the free into the bound form of geldanamycin. In the superimpositions, the initial structures are colored in yellow, and the final structures are colored in cyan. The intermediate conformations are explicitly shown. For clarity, only the polar hydrogens are shown.
 
  The above figures are reprinted by permission from Cell Press: Chem Biol (2003, 10, 361-368) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21531051 S.Sakkiah, S.Thangapandian, S.John, and K.W.Lee (2011).
Pharmacophore based virtual screening, molecular docking studies to design potent heat shock protein 90 inhibitors.
  Eur J Med Chem, 46, 2937-2947.  
19300478 G.Morra, G.Verkhivker, and G.Colombo (2009).
Modeling signal propagation mechanisms and ligand-based conformational dynamics of the Hsp90 molecular chaperone full-length dimer.
  PLoS Comput Biol, 5, e1000323.  
19492825 M.K.Hadden, and B.S.Blagg (2009).
Synthesis and evaluation of radamide analogues, a chimera of radicicol and geldanamycin.
  J Org Chem, 74, 4697-4704.  
19788917 M.R.Hutchinson, K.M.Ramos, L.C.Loram, J.Wieseler, P.W.Sholar, J.J.Kearney, M.T.Lewis, N.Y.Crysdale, Y.Zhang, J.A.Harrison, S.F.Maier, K.C.Rice, and L.R.Watkins (2009).
Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats.
  Neuroscience, 164, 1821-1832.  
19685544 M.Sgobba, and G.Rastelli (2009).
Structure-based and in silico design of Hsp90 inhibitors.
  ChemMedChem, 4, 1399-1409.  
19200020 M.W.Amolins, and B.S.Blagg (2009).
Natural product inhibitors of Hsp90: potential leads for drug discovery.
  Mini Rev Med Chem, 9, 140-152.  
19017562 T.Taldone, W.Sun, and G.Chiosis (2009).
Discovery and development of heat shock protein 90 inhibitors.
  Bioorg Med Chem, 17, 2225-2235.  
19896848 V.D.Jadhav, A.S.Duerfeldt, and B.S.Blagg (2009).
Design, synthesis, and biological activity of bicyclic radester analogues as Hsp90 inhibitors.
  Bioorg Med Chem Lett, 19, 6845-6850.  
18287101 A.Leskovar, H.Wegele, N.D.Werbeck, J.Buchner, and J.Reinstein (2008).
The ATPase cycle of the mitochondrial Hsp90 analog Trap1.
  J Biol Chem, 283, 11677-11688.  
18826913 A.Yan, G.H.Grant, and W.G.Richards (2008).
Dynamics of conserved waters in human Hsp90: implications for drug design.
  J R Soc Interface, 5, S199-S205.  
18175003 K.Lee, J.S.Ryu, Y.Jin, W.Kim, N.Kaur, S.J.Chung, Y.J.Jeon, J.T.Park, J.S.Bang, H.S.Lee, T.Y.Kim, J.J.Lee, and Y.S.Hong (2008).
Synthesis and anticancer activity of geldanamycin derivatives derived from biosynthetically generated metabolites.
  Org Biomol Chem, 6, 340-348.  
18497896 M.S.Butler (2008).
Natural products to drugs: natural product-derived compounds in clinical trials.
  Nat Prod Rep, 25, 475-516.  
18373550 M.Sgobba, G.Degliesposti, A.M.Ferrari, and G.Rastelli (2008).
Structural models and binding site prediction of the C-terminal domain of human Hsp90: a new target for anticancer drugs.
  Chem Biol Drug Des, 71, 420-433.  
17252137 C.S.McErlean, N.Proisy, C.J.Davis, N.A.Boland, S.Y.Sharp, K.Boxall, A.M.Slawin, P.Workman, and C.J.Moody (2007).
Synthetic ansamycins prepared by a ring-expanding Claisen rearrangement. Synthesis and biological evaluation of ring and conformational analogues of the Hsp90 molecular chaperone inhibitor geldanamycin.
  Org Biomol Chem, 5, 531-546.  
17804463 M.Stahl, M.Retzlaff, M.Nassal, and J.Beck (2007).
Chaperone activation of the hepadnaviral reverse transcriptase for template RNA binding is established by the Hsp70 and stimulated by the Hsp90 system.
  Nucleic Acids Res, 35, 6124-6136.  
17565155 S.H.Oh, J.K.Woo, Y.D.Yazici, J.N.Myers, W.Y.Kim, Q.Jin, S.S.Hong, H.J.Park, Y.G.Suh, K.W.Kim, W.K.Hong, and H.Y.Lee (2007).
Structural basis for depletion of heat shock protein 90 client proteins by deguelin.
  J Natl Cancer Inst, 99, 949-961.  
17055434 A.K.Shiau, S.F.Harris, D.R.Southworth, and D.A.Agard (2006).
Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements.
  Cell, 127, 329-340.
PDB codes: 2gq0 2iop 2ioq 2ior
16540363 A.Orosz, A.Szabo, G.Szeman, T.Janaky, C.Somlai, B.Penke, A.Bodor, and A.Perczel (2006).
Novel nontoxic heat shock protein 90 inhibitors having selective antiproliferative effect.
  Int J Biochem Cell Biol, 38, 1352-1362.  
16385472 B.S.Blagg, and T.D.Kerr (2006).
Hsp90 inhibitors: small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation.
  Med Res Rev, 26, 310-338.  
16687576 C.Y.Chen, and W.E.Balch (2006).
The Hsp90 chaperone complex regulates GDI-dependent Rab recycling.
  Mol Biol Cell, 17, 3494-3507.  
17009903 H.N.Banerjee, and M.Verma (2006).
Use of nanotechnology for the development of novel cancer biomarkers.
  Expert Rev Mol Diagn, 6, 679-683.  
17090671 J.R.Sydor, E.Normant, C.S.Pien, J.R.Porter, J.Ge, L.Grenier, R.H.Pak, J.A.Ali, M.S.Dembski, J.Hudak, J.Patterson, C.Penders, M.Pink, M.A.Read, J.Sang, C.Woodward, Y.Zhang, D.S.Grayzel, J.Wright, J.A.Barrett, V.J.Palombella, J.Adams, and J.K.Tong (2006).
Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.
  Proc Natl Acad Sci U S A, 103, 17408-17413.  
16565516 M.A.Martinez-Yamout, R.P.Venkitakrishnan, N.E.Preece, G.Kroon, P.E.Wright, and H.J.Dyson (2006).
Localization of sites of interaction between p23 and Hsp90 in solution.
  J Biol Chem, 281, 14457-14464.  
17066389 S.Chaudhury, T.R.Welch, and B.S.Blagg (2006).
Hsp90 as a target for drug development.
  ChemMedChem, 1, 1331-1340.  
15778971 D.G.Covell, A.Wallqvist, R.Huang, N.Thanki, A.A.Rabow, and X.J.Lu (2005).
Linking tumor cell cytotoxicity to mechanism of drug action: an integrated analysis of gene expression, small-molecule screening and structural databases.
  Proteins, 59, 403-433.  
16555999 G.V.Georgakis, and A.Younes (2005).
Heat-shock protein 90 inhibitors in cancer therapy: 17AAG and beyond.
  Future Oncol, 1, 273-281.  
16118214 J.J.Hung, C.Y.Wu, P.C.Liao, and W.C.Chang (2005).
Hsp90alpha recruited by Sp1 is important for transcription of 12(S)-lipoxygenase in A431 cells.
  J Biol Chem, 280, 36283-36292.  
15338192 J.L.Eiseman, J.Lan, T.F.Lagattuta, D.R.Hamburger, E.Joseph, J.M.Covey, and M.J.Egorin (2005).
Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts.
  Cancer Chemother Pharmacol, 55, 21-32.  
16086635 K.K.Jain (2005).
Personalised medicine for cancer: from drug development into clinical practice.
  Expert Opin Pharmacother, 6, 1463-1476.  
15791458 M.Hollingshead, M.Alley, A.M.Burger, S.Borgel, C.Pacula-Cox, H.H.Fiebig, and E.A.Sausville (2005).
In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative.
  Cancer Chemother Pharmacol, 56, 115-125.  
15806196 M.S.Butler (2005).
Natural products to drugs: natural product derived compounds in clinical trials.
  Nat Prod Rep, 22, 162-195.  
15837196 Q.Huai, H.Wang, Y.Liu, H.Y.Kim, D.Toft, and H.Ke (2005).
Structures of the N-terminal and middle domains of E. coli Hsp90 and conformation changes upon ADP binding.
  Structure, 13, 579-590.
PDB codes: 1y4s 1y4u
15177193 A.Kamal, M.F.Boehm, and F.J.Burrows (2004).
Therapeutic and diagnostic implications of Hsp90 activation.
  Trends Mol Med, 10, 283-290.  
15106614 P.Workman (2004).
Altered states: selectively drugging the Hsp90 cancer chaperone.
  Trends Mol Med, 10, 47-51.  
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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