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PDBsum entry 1uyc
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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-alpha with 9-butyl-8-(2,5-dimethoxy-benzyl)-9h-purin-6- ylamine
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Structure:
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Heat shock protein hsp 90-alpha. Chain: a. Fragment: n-terminal domain, residues 1-235. 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. Expression_system_taxid: 469008. Other_details: cloned from image\:4026275
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Resolution:
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2.00Å
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R-factor:
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0.186
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R-free:
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0.248
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Authors:
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L.Wright,X.Barril,B.Dymock,L.Sheridan,A.Surgenor,M.Beswick, M.Drysdale,A.Collier,A.Massey,N.Davies,A.Fink,C.Fromont,W.Aherne, K.Boxall,S.Sharp,P.Workman,R.E.Hubbard
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Key ref:
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L.Wright
et al.
(2004).
Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms.
Chem Biol,
11,
775-785.
PubMed id:
DOI:
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Date:
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02-Mar-04
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Release date:
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01-Jul-04
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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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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
Bound ligand (Het Group name = )
matches with 44.44% similarity
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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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Chem Biol
11:775-785
(2004)
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PubMed id:
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Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms.
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L.Wright,
X.Barril,
B.Dymock,
L.Sheridan,
A.Surgenor,
M.Beswick,
M.Drysdale,
A.Collier,
A.Massey,
N.Davies,
A.Fink,
C.Fromont,
W.Aherne,
K.Boxall,
S.Sharp,
P.Workman,
R.E.Hubbard.
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ABSTRACT
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Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential
strategy for treatment of cancers. We have determined structures of the
HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and
analogs with enhanced potency both in enzyme and cell-based assays. The
compounds induce upregulation of HSP70 and downregulation of the known HSP90
client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit
cell growth by a mechanism dependent on HSP90 inhibition. We have also
determined the first structure of the N-terminal domain of HSP90beta, complexed
with PU3. The structures allow a detailed rationale to be developed for the
observed affinity of the PU3 class of compounds for HSP90 and also provide a
structural framework for design of compounds with improved binding affinity and
drug-like properties.
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Selected figure(s)
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Figure 2.
Figure 2. PU3 Binding to HSP90Schematic of interactions
between PU3 and the binding site of Nt-HSP90α (figure produced
using Ligplot, [32]).
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Figure 4.
Figure 4. Purine Analogs and Enzyme Inhibition Data
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2004,
11,
775-785)
copyright 2004.
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Figures were
selected
by an automated process.
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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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E.S.Pires,
A.K.Choudhury,
S.Idicula-Thomas,
and
V.V.Khole
(2011).
Anti-HSP90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380-389) of HSP90 beta protein.
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Reprod Biol Endocrinol,
9,
16.
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K.K.Roy,
S.Singh,
and
A.K.Saxena
(2011).
Integration-mediated prediction enrichment of quantitative model for Hsp90 inhibitors as anti-cancer agents: 3D-QSAR study.
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Mol Divers,
15,
477-489.
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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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E.Pozharski
(2010).
Percentile-based spread: a more accurate way to compare crystallographic models.
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Acta Crystallogr D Biol Crystallogr,
66,
970-978.
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P.Fadden,
K.H.Huang,
J.M.Veal,
P.M.Steed,
A.F.Barabasz,
B.Foley,
M.Hu,
J.M.Partridge,
J.Rice,
A.Scott,
L.G.Dubois,
T.A.Freed,
M.A.Silinski,
T.E.Barta,
P.F.Hughes,
A.Ommen,
W.Ma,
E.D.Smith,
A.W.Spangenberg,
J.Eaves,
G.J.Hanson,
L.Hinkley,
M.Jenks,
M.Lewis,
J.Otto,
G.J.Pronk,
K.Verleysen,
T.A.Haystead,
and
S.E.Hall
(2010).
Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90.
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Chem Biol,
17,
686-694.
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PDB code:
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S.Tomaselli,
M.Meli,
J.Plescia,
L.Zetta,
D.C.Altieri,
G.Colombo,
and
L.Ragona
(2010).
Combined in silico and experimental approach for drug design: the binding mode of peptidic and non-peptidic inhibitors to hsp90 N-terminal domain.
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Chem Biol Drug Des,
76,
382-391.
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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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M.W.Amolins,
and
B.S.Blagg
(2009).
Natural product inhibitors of Hsp90: potential leads for drug discovery.
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Mini Rev Med Chem,
9,
140-152.
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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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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.
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Chembiochem,
10,
2753-2759.
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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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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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A.Chadli,
S.J.Felts,
and
D.O.Toft
(2008).
GCUNC45 is the first Hsp90 co-chaperone to show alpha/beta isoform specificity.
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J Biol Chem,
283,
9509-9512.
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A.Yan,
G.H.Grant,
and
W.G.Richards
(2008).
Dynamics of conserved waters in human Hsp90: implications for drug design.
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J R Soc Interface,
5,
S199-S205.
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W.Y.Chen,
F.R.Chang,
Z.Y.Huang,
J.H.Chen,
Y.C.Wu,
and
C.C.Wu
(2008).
Tubocapsenolide A, a novel withanolide, inhibits proliferation and induces apoptosis in MDA-MB-231 cells by thiol oxidation of heat shock proteins.
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J Biol Chem,
283,
17184-17193.
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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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J.R.Huth,
C.Park,
A.M.Petros,
A.R.Kunzer,
M.D.Wendt,
X.Wang,
C.L.Lynch,
J.C.Mack,
K.M.Swift,
R.A.Judge,
J.Chen,
P.L.Richardson,
S.Jin,
S.K.Tahir,
E.D.Matayoshi,
S.A.Dorwin,
U.S.Ladror,
J.M.Severin,
K.A.Walter,
D.M.Bartley,
S.W.Fesik,
S.W.Elmore,
and
P.J.Hajduk
(2007).
Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.
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Chem Biol Drug Des,
70,
1.
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PDB codes:
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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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T.C.Terwilliger,
R.W.Grosse-Kunstleve,
P.V.Afonine,
P.D.Adams,
N.W.Moriarty,
P.Zwart,
R.J.Read,
D.Turk,
and
L.W.Hung
(2007).
Interpretation of ensembles created by multiple iterative rebuilding of macromolecular models.
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Acta Crystallogr D Biol Crystallogr,
63,
597-610.
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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.
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Int J Biochem Cell Biol,
38,
1352-1362.
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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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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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T.C.Terwilliger,
H.Klei,
P.D.Adams,
N.W.Moriarty,
and
J.D.Cohn
(2006).
Automated ligand fitting by core-fragment fitting and extension into density.
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Acta Crystallogr D Biol Crystallogr,
62,
915-922.
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A.Hardcastle,
K.Boxall,
J.Richards,
P.Tomlin,
S.Sharp,
P.Clarke,
P.Workman,
and
W.Aherne
(2005).
Solid-phase immunoassays in mechanism-based drug discovery: their application in the development of inhibitors of the molecular chaperone heat-shock protein 90.
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Assay Drug Dev Technol,
3,
273-285.
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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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G.Chiosis,
M.Vilenchik,
J.Kim,
and
D.Solit
(2004).
Hsp90: the vulnerable chaperone.
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Drug Discov Today,
9,
881-888.
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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
