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PDBsum entry 5aqz
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PDB id:
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Chaperone
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Title:
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Hsp72 with adenosine-derived inhibitor
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Structure:
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Heat shock 70 kda protein 1a. Chain: a. Fragment: nucleotide binding domain, unp residues 1-380. Synonym: heat shock 70 kda protein 1, hsp70-1, hsp70.1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: ai.
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Resolution:
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1.65Å
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R-factor:
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0.188
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R-free:
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0.221
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Authors:
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M.D.Cheeseman,I.M.Westwood,O.Barbeau,M.G.Rowlands,A.M.Jones, F.Jeganathan,R.Burke,S.E.Dobson,P.Workman,I.Collins,R.L.M.Van Montfort,K.Jones
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Key ref:
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M.D.Cheeseman
et al.
(2016).
Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.
J Med Chem,
59,
4625-4636.
PubMed id:
DOI:
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Date:
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22-Sep-15
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Release date:
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11-May-16
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PROCHECK
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Headers
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References
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P0DMV8
(HS71A_HUMAN) -
Heat shock 70 kDa protein 1A from Homo sapiens
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Seq:
Struc:
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641 a.a.
390 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 8 residue positions (black
crosses)
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Enzyme class:
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E.C.3.6.3.51
- Transferred entry: 7.4.2.3.
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Reaction:
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ATP + H2O = ADP + phosphate
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ATP
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+
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H(2)O
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=
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ADP
Bound ligand (Het Group name = )
matches with 58.06% similarity
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+
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phosphate
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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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J Med Chem
59:4625-4636
(2016)
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PubMed id:
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Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.
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M.D.Cheeseman,
I.M.Westwood,
O.Barbeau,
M.Rowlands,
S.Dobson,
A.M.Jones,
F.Jeganathan,
R.Burke,
N.Kadi,
P.Workman,
I.Collins,
R.L.van Montfort,
K.Jones.
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ABSTRACT
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HSP70 is a molecular chaperone and a key component of the heat-shock response.
Because of its proposed importance in oncology, this protein has become a
popular target for drug discovery, efforts which have as yet brought little
success. This study demonstrates that adenosine-derived HSP70 inhibitors
potentially bind to the protein with a novel mechanism of action, the
stabilization by desolvation of an intramolecular salt-bridge which induces a
conformational change in the protein, leading to high affinity ligands. We also
demonstrate that through the application of this mechanism, adenosine-derived
HSP70 inhibitors can be optimized in a rational manner.
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Links
