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PDBsum entry 5aql
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References listed in PDB file
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Key reference
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Title
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A fragment-Based approach applied to a highly flexible target: insights and challenges towards the inhibition of hsp70 isoforms.
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Authors
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A.M.Jones,
I.M.Westwood,
J.D.Osborne,
T.P.Matthews,
M.D.Cheeseman,
M.G.Rowlands,
F.Jeganathan,
R.Burke,
D.Lee,
N.Kadi,
M.Liu,
M.Richards,
C.Mcandrew,
N.Yahya,
S.E.Dobson,
K.Jones,
P.Workman,
I.Collins,
R.L.Van montfort.
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Ref.
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Sci Rep, 2016,
6,
34701.
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PubMed id
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Abstract
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The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many
cancers and of significant interest as targets for novel cancer therapies.
Several HSP70 inhibitors have been reported, but because the majority have poor
physicochemical properties and for many the exact mode of action is poorly
understood, more detailed mechanistic and structural insight into ligand-binding
to HSP70s is urgently needed. Here we describe the first comprehensive
fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an
amino-quinazoline fragment that was elaborated to a novel ATP binding site
ligand with different physicochemical properties to known adenosine-based HSP70
inhibitors. Crystal structures of amino-quinazoline ligands bound to the
different conformational states of the HSP70 nucleotide binding domain
highlighted the challenges of a fragment-based approach when applied to this
particular flexible enzyme class with an ATP-binding site that changes shape and
size during its catalytic cycle. In these studies we showed that Ser275 is a key
residue in the selective binding of ATP. Additionally, the structural data
revealed a potential functional role for the ATP ribose moiety in priming the
protein for the formation of the ATP-bound pre-hydrolysis complex by influencing
the conformation of one of the phosphate binding loops.
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