title: Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones.
abstract: Hsp70 (heat shock protein 70 kDa) chaperones are key to cellular protein homeostasis. However, they also have the ability to inhibit tumor apoptosis and contribute to aberrant accumulation of hyperphosphorylated tau in neuronal cells affected by tauopathies, including Alzheimer's disease. Hence, Hsp70 chaperones are increasingly becoming identified as targets for therapeutic intervention in these widely abundant diseases. Hsp70 proteins are allosteric machines and offer, besides classical active-site targets, also opportunities to target the mechanism of allostery. In this work, it is demonstrated that the action of the potent anticancer compound MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-oxothiazolidin-2-ylidenemethyl] pyridinium chloride) occurs through a differential interaction with Hsp70 allosteric states. MKT-077 is therefore an "allosteric drug." Using NMR spectroscopy, we identify the compound's binding site on human HSPA8 (Hsc70). The binding pose is obtained from NMR-restrained docking calculations, subsequently scored by molecular-dynamics-based energy and solvation computations. Suggestions for the improvement of the compound's properties are made on the basis of the binding location and pose.
authors.affiliation: Program in Biophysics, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Rousaki
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyata
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Erik R P
authors.initials: ER
authors.lastname: Zuiderweg
mesh_terms: D001665:Binding Sites; D004926:Escherichia coli / Q000235:genetics; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018832:Molecular Chaperones; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology*; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D018832:Molecular Chaperones; D011725:Pyridines; D013844:Thiazoles; C097880:MKT 077