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PDBsum entry 2ccs
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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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Human hsp90 with 4-chloro-6-(4-piperazin-1-yl-1h-pyrazol-3-yl)- benzene-1,2-diol
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Structure:
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Heat shock protein hsp-90 alpha. Chain: a. Fragment: n-terminal domain residues 1-236. Synonym: hsp 86. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Organ: skin. Tissue: melanoma. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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1.79Å
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R-factor:
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0.229
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R-free:
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0.277
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Authors:
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X.Barril,M.C.Beswick,A.Collier,M.J.Drysdale,B.W.Dymock,A.Fink, K.Grant,R.Howes,A.M.Jordan,A.Massey,A.Surgenor,J.Wayne,P.Workman, L.Wright
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Key ref:
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X.Barril
et al.
(2006).
4-Amino derivatives of the Hsp90 inhibitor CCT018159.
Bioorg Med Chem Lett,
16,
2543-2548.
PubMed id:
DOI:
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Date:
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18-Jan-06
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Release date:
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22-Feb-06
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PROCHECK
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Headers
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References
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P07900
(HS90A_HUMAN) -
Heat shock protein HSP 90-alpha from Homo sapiens
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Seq:
Struc:
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732 a.a.
209 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.3.6.4.10
- non-chaperonin molecular chaperone ATPase.
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Reaction:
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ATP + H2O = ADP + phosphate + H+
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ATP
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+
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H2O
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=
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ADP
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+
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phosphate
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
16:2543-2548
(2006)
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PubMed id:
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4-Amino derivatives of the Hsp90 inhibitor CCT018159.
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X.Barril,
M.C.Beswick,
A.Collier,
M.J.Drysdale,
B.W.Dymock,
A.Fink,
K.Grant,
R.Howes,
A.M.Jordan,
A.Massey,
A.Surgenor,
J.Wayne,
P.Workman,
L.Wright.
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ABSTRACT
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Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based
Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have
been elucidated by X-ray co-crystal analysis of the new compounds bound to the
N-terminal domain of human Hsp90. Key features of the binding mode are
essentially identical to the recently reported potent analogue VER-49009. The
most potent of the new compounds has a methylsulfonylbenzyl substituent appended
to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding
against the enzyme and demonstrates low micromolar inhibition of tumour cell
proliferation.
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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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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.
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Eur J Med Chem,
46,
2937-2947.
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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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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.
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PLoS Comput Biol,
5,
e1000323.
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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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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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R.Martinez,
J.P.Genet,
and
S.Darses
(2008).
Anti-Markovnikov hydroarylation of styrenes catalyzed by an in situ generated ruthenium complex.
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Chem Commun (Camb),
(),
3855-3857.
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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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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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L.Galam,
M.K.Hadden,
Z.Ma,
Q.Z.Ye,
B.G.Yun,
B.S.Blagg,
and
R.L.Matts
(2007).
High-throughput assay for the identification of Hsp90 inhibitors based on Hsp90-dependent refolding of firefly luciferase.
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Bioorg Med Chem,
15,
1939-1946.
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J.B.Lattouf,
R.Srinivasan,
P.A.Pinto,
W.M.Linehan,
and
L.Neckers
(2006).
Mechanisms of disease: the role of heat-shock protein 90 in genitourinary malignancy.
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Nat Clin Pract Urol,
3,
590-601.
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S.Chaudhury,
T.R.Welch,
and
B.S.Blagg
(2006).
Hsp90 as a target for drug development.
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ChemMedChem,
1,
1331-1340.
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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
codes are
shown on the right.
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Links
