PDBsum entry 2iwu

Chaperone

PDB id

2iwu

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Contents

			Protein chain

					214 a.a. *

			Ligands

					NP5

			Waters ×6

* Residue conservation analysis

PDB id:

2iwu

Links

Name:

Chaperone

Title:

Analogues of radicicol bound to the atp-binding site of hsp90

Structure:

Atp-dependent molecular chaperone hsp82. Chain: a. Fragment: n terminal domain, residues 1-214. Synonym: heat shock protein 90 heat-inducible isoform, 82 kda heat shock protein. Engineered: yes

Source:

Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Monomer (from PDB file)

Resolution:

2.80Å

R-factor:

0.232

R-free:

0.291

Authors:

S.M.Roe,C.Prodromou,L.H.Pearl

Key ref:

N.Proisy et al. (2006). Inhibition of hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chem Biol, 13, 1203-1215. PubMed id: 17114002 DOI: 10.1016/j.chembiol.2006.09.015

Date:

04-Jul-06

Release date:

30-Nov-06

PROCHECK

	Headers

	References

Protein chain

P02829 (HSP82_YEAST) - ATP-dependent molecular chaperone HSP82 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: Struc:

Seq: Struc:					709 a.a. 214 a.a.

Key:

PfamA domain

Secondary structure

CATH domain

DOI no: 10.1016/j.chembiol.2006.09.015	Chem Biol 13:1203-1215 (2006)
PubMed id: 17114002

Inhibition of hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol.
N.Proisy, S.Y.Sharp, K.Boxall, S.Connelly, S.M.Roe, C.Prodromou, A.M.Slawin, L.H.Pearl, P.Workman, C.J.Moody.

ABSTRACT

A series of benzo-macrolactones of varying ring size and conformation has been prepared by chemical synthesis and evaluated by structural and biological techniques. Thus, 12- to 16-membered lactones were obtained by concise routes, involving ring-closing metathesis as a key step. In enzyme assays, the 13-, 15-, and 16-membered analogs are good inhibitors, suggesting that they can adopt the required conformation to fit in the ATP-binding site. This was confirmed by cocrystallization of 13-, 14-, and 15-membered lactones with the N-terminal domain of yeast Hsp90, showing that they bind similarly to the "natural" 14-membered radicicol. The most active compounds in the ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human colon cancer cells and the established molecular signature of Hsp90 inhibition, i.e., depletion of client proteins with upregulation of Hsp70.

Selected figure(s)



	Figure 2. Figure 2. Binding Interactions of Macrolactone Inhibitors with Yeast Hsp90		Figure 5. Figure 5. Molecular Modeling

Figures were selected by the author.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21050069

M.T.Guarnieri, B.S.Blagg, and R.Zhao (2011).
A high-throughput TNP-ATP displacement assay for screening inhibitors of ATP-binding in bacterial histidine kinases.

Assay Drug Dev Technol, 9, 174-183.

20981667

C.Rink, F.Sasse, A.Zubrienė, D.Matulis, and M.E.Maier (2010).
Probing the influence of an allylic methyl group in zearalenone analogues on binding to Hsp90.

Chemistry, 16, 14469-14478.

20087915

J.E.Day, S.Y.Sharp, M.G.Rowlands, W.Aherne, P.Workman, and C.J.Moody (2010).
Targeting the Hsp90 chaperone: synthesis of novel resorcylic acid macrolactone inhibitors of Hsp90.

Chemistry, 16, 2758-2763.

20661961

J.E.Day, S.Y.Sharp, M.G.Rowlands, W.Aherne, W.Lewis, S.M.Roe, C.Prodromou, L.H.Pearl, P.Workman, and C.J.Moody (2010).
Inhibition of Hsp90 with resorcylic acid macrolactones: synthesis and binding studies.

Chemistry, 16, 10366-10372.

PDB code:

2xd6

19637143

M.Ugele, F.Sasse, S.Knapp, O.Fedorov, A.Zubriene, D.Matulis, and M.E.Maier (2009).
Propionate analogues of zearalenone bind to Hsp90.

Chembiochem, 10, 2203-2212.

19856365

S.Barluenga, J.G.Fontaine, C.Wang, K.Aouadi, R.Chen, K.Beebe, L.Neckers, and N.Winssinger (2009).
Inhibition of HSP90 with pochoximes: SAR and structure-based insights.

Chembiochem, 10, 2753-2759.

PDB codes:

3inw 3inx

19179103

Y.Li, T.Zhang, S.J.Schwartz, and D.Sun (2009).
New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential.

Drug Resist Updat, 12, 17-27.

18435518

S.Barluenga, C.Wang, J.G.Fontaine, K.Aouadi, K.Beebe, S.Tsutsumi, L.Neckers, and N.Winssinger (2008).
Divergent synthesis of a pochonin library targeting HSP90 and in vivo efficacy of an identified inhibitor.

Angew Chem Int Ed Engl, 47, 4432-4435.

18256191

T.A.Hawkins, A.P.Haramis, C.Etard, C.Prodromou, C.K.Vaughan, R.Ashworth, S.Ray, M.Behra, N.Holder, W.S.Talbot, L.H.Pearl, U.Strähle, and S.W.Wilson (2008).
The ATPase-dependent chaperoning activity of Hsp90a regulates thick filament formation and integration during skeletal muscle myofibrillogenesis.

Development, 135, 1147-1156.

18571929

T.Ganesh, J.Min, P.Thepchatri, Y.Du, L.Li, I.Lewis, L.Wilson, H.Fu, G.Chiosis, R.Dingledine, D.Liotta, J.P.Snyder, and A.Sun (2008).
Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein 90 (Hsp90): Synthesis, biology, and molecular modeling.

Bioorg Med Chem, 16, 6903-6910.

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.

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 code is shown on the right.