Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.
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.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Matthew D
MD
Cheeseman
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.|Division of Structural Biology, The Institute of Cancer Research , London SW7 3RP, U.K.
Isaac M
IM
Westwood
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Olivier
O
Barbeau
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Martin
M
Rowlands
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.|Division of Structural Biology, The Institute of Cancer Research , London SW7 3RP, U.K.
Sarah
S
Dobson
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Alan M
AM
Jones
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Fiona
F
Jeganathan
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Rosemary
R
Burke
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Nadia
N
Kadi
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Paul
P
Workman
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Ian
I
Collins
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.|Division of Structural Biology, The Institute of Cancer Research , London SW7 3RP, U.K.
Rob L M
RL
van Montfort
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
Keith
K
Jones
D000241:Adenosine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D018840:HSP70 Heat-Shock Proteins; D000241:Adenosine