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PDBsum entry 2brc
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Contents |
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* Residue conservation analysis
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PDB id:
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Chaperone
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Title:
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Structure of a hsp90 inhibitor bound to the n-terminus of yeast hsp90.
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Structure:
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Atp-dependent molecular chaperone hsp82. Chain: a. Fragment: n-terminus, residues 1-214. Synonym: hsp90,heat shock protein hsp90,82 kda heat shock protein. Engineered: yes
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Source:
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Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.60Å
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R-factor:
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0.188
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R-free:
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0.214
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Authors:
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S.M.Roe,L.H.Pearl,C.Prodromou
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Key ref:
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K.M.Cheung
et al.
(2005).
The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors.
Bioorg Med Chem Lett,
15,
3338-3343.
PubMed id:
DOI:
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Date:
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04-May-05
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Release date:
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29-Sep-05
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PROCHECK
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Headers
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References
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P02829
(HSP82_YEAST) -
ATP-dependent molecular chaperone HSP82 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
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Seq:
Struc:
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709 a.a.
214 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Bioorg Med Chem Lett
15:3338-3343
(2005)
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PubMed id:
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The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors.
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K.M.Cheung,
T.P.Matthews,
K.James,
M.G.Rowlands,
K.J.Boxall,
S.Y.Sharp,
A.Maloney,
S.M.Roe,
C.Prodromou,
L.H.Pearl,
G.W.Aherne,
E.McDonald,
P.Workman.
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ABSTRACT
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High-throughput screening identified the 3,4-diarylpyrazole CCT018159 as a novel
and potent (7.1 microM) inhibitor of Hsp90 ATPase activity. Here, we describe
the synthesis of CCT018159 and a number of close analogues together with data on
their biochemical properties. Some initial structure-activity relationships are
discussed, as well as the crystal structure of CCT018159 bound to Hsp90.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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T.Taldone,
D.Zatorska,
P.D.Patel,
H.Zong,
A.Rodina,
J.H.Ahn,
K.Moulick,
M.L.Guzman,
and
G.Chiosis
(2011).
Design, synthesis, and evaluation of small molecule Hsp90 probes.
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Bioorg Med Chem,
19,
2603-2614.
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M.Beloueche-Babari,
V.Arunan,
L.E.Jackson,
N.Perusinghe,
S.Y.Sharp,
P.Workman,
and
M.O.Leach
(2010).
Modulation of melanoma cell phospholipid metabolism in response to heat shock protein 90 inhibition.
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Oncotarget,
1,
185-197.
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N.Gaspar,
S.Y.Sharp,
S.A.Eccles,
S.Gowan,
S.Popov,
C.Jones,
A.Pearson,
G.Vassal,
and
P.Workman
(2010).
Mechanistic evaluation of the novel HSP90 inhibitor NVP-AUY922 in adult and pediatric glioblastoma.
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Mol Cancer Ther,
9,
1219-1233.
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P.Workman,
and
I.Collins
(2010).
Probing the probes: fitness factors for small molecule tools.
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Chem Biol,
17,
561-577.
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C.Rajesh,
A.M.Gruver,
V.Basrur,
and
D.L.Pittman
(2009).
The interaction profile of homologous recombination repair proteins RAD51C, RAD51D and XRCC2 as determined by proteomic analysis.
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Proteomics,
9,
4071-4086.
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G.E.de Kloe,
D.Bailey,
R.Leurs,
and
I.J.de Esch
(2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
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Drug Discov Today,
14,
630-646.
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M.Anzaldi,
C.Macciò,
M.Mazzei,
M.Bertolotto,
L.Ottonello,
F.Dallegri,
and
A.Balbi
(2009).
Antiproliferative and proapoptotic activities of a new class of pyrazole derivatives in HL-60 cells.
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Chem Biodivers,
6,
1674-1687.
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M.K.Hadden,
S.A.Hill,
J.Davenport,
R.L.Matts,
and
B.S.Blagg
(2009).
Synthesis and evaluation of Hsp90 inhibitors that contain the 1,4-naphthoquinone scaffold.
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Bioorg Med Chem,
17,
634-640.
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M.Sgobba,
and
G.Rastelli
(2009).
Structure-based and in silico design of Hsp90 inhibitors.
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ChemMedChem,
4,
1399-1409.
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R.I.Feldman,
B.Mintzer,
D.Zhu,
J.M.Wu,
S.L.Biroc,
S.Yuan,
K.Emayan,
Z.Chang,
D.Chen,
D.O.Arnaiz,
J.Bryant,
X.S.Ge,
M.Whitlow,
M.Adler,
M.A.Polokoff,
W.W.Li,
M.Ferrer,
T.Sato,
J.M.Gu,
J.Shen,
J.L.Tseng,
H.Dinter,
and
B.Buckman
(2009).
Potent triazolothione inhibitor of heat-shock protein-90.
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Chem Biol Drug Des,
74,
43-50.
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PDB code:
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R.L.van Montfort,
and
P.Workman
(2009).
Structure-based design of molecular cancer therapeutics.
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Trends Biotechnol,
27,
315-328.
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R.M.Immormino,
L.E.Metzger,
P.N.Reardon,
D.E.Dollins,
B.S.Blagg,
and
D.T.Gewirth
(2009).
Different poses for ligand and chaperone in inhibitor-bound Hsp90 and GRP94: implications for paralog-specific drug design.
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J Mol Biol,
388,
1033-1042.
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PDB codes:
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T.Taldone,
W.Sun,
and
G.Chiosis
(2009).
Discovery and development of heat shock protein 90 inhibitors.
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Bioorg Med Chem,
17,
2225-2235.
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V.Giansanti,
T.Camboni,
F.Piscitelli,
E.Prosperi,
G.La Regina,
M.C.Lazzè,
G.Santin,
R.Silvestri,
and
A.I.Scovassi
(2009).
Study of the effects of a new pyrazolecarboxamide: changes in mitochondria and induction of apoptosis.
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Int J Biochem Cell Biol,
41,
1890-1898.
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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.
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Drug Resist Updat,
12,
17-27.
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R.E.Hubbard
(2008).
Fragment approaches in structure-based drug discovery.
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J Synchrotron Radiat,
15,
227-230.
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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.
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Bioorg Med Chem,
16,
6903-6910.
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T.Ganesh,
P.Thepchatri,
L.Li,
Y.Du,
H.Fu,
J.P.Snyder,
and
A.Sun
(2008).
Synthesis and SAR study of N-(4-hydroxy-3-(2-hydroxynaphthalene-1-yl)phenyl)-arylsulfonamides: heat shock protein 90 (Hsp90) inhibitors with submicromolar activity in an in vitro assay.
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Bioorg Med Chem Lett,
18,
4982-4987.
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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.
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Org Biomol Chem,
5,
531-546.
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G.Bossi,
and
A.Sacchi
(2007).
Restoration of wild-type p53 function in human cancer: relevance for tumor therapy.
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Head Neck,
29,
272-284.
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L.Neckers
(2007).
Heat shock protein 90: the cancer chaperone.
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J Biosci,
32,
517-530.
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P.Workman,
F.Burrows,
L.Neckers,
and
N.Rosen
(2007).
Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress.
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Ann N Y Acad Sci,
1113,
202-216.
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I.Collins,
and
P.Workman
(2006).
New approaches to molecular cancer therapeutics.
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Nat Chem Biol,
2,
689-700.
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M.M.Ali,
S.M.Roe,
C.K.Vaughan,
P.Meyer,
B.Panaretou,
P.W.Piper,
C.Prodromou,
and
L.H.Pearl
(2006).
Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.
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Nature,
440,
1013-1017.
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PDB codes:
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M.W.Graner,
and
D.D.Bigner
(2006).
Therapeutic aspects of chaperones/heat-shock proteins in neuro-oncology.
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Expert Rev Anticancer Ther,
6,
679-695.
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P.K.Majumder,
and
W.R.Sellers
(2005).
Akt-regulated pathways in prostate cancer.
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Oncogene,
24,
7465-7474.
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P.Workman
(2005).
Drugging the cancer kinome: progress and challenges in developing personalized molecular cancer therapeutics.
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Cold Spring Harb Symp Quant Biol,
70,
499-515.
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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.
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Links
