 |
PDBsum entry 1uyh
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure-Activity relationships in purine-Based inhibitor binding to hsp90 isoforms.
|
|
|
Authors
|
|
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.
|
|
|
Ref.
|
|
Chem Biol, 2004,
11,
775-785.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
|
|
|
|
|
Figure 2.
Figure 2. PU3 Binding to HSP90Schematic of interactions
between PU3 and the binding site of Nt-HSP90α (figure produced
using Ligplot, [32]).
|
|
Figure 4.
Figure 4. Purine Analogs and Enzyme Inhibition Data
|
|
|
|
|
|
The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2004,
11,
775-785)
copyright 2004.
|
|
|
|
|
|
|
