Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones |
| |
Authors: | Rousaki Aikaterini Miyata Yoshinari Jinwal Umesh K Dickey Chad A Gestwicki Jason E Zuiderweg Erik R P |
| |
Affiliation: | 1 Program in Biophysics, The University of Michigan, Ann Arbor, MI 48109, USA2 Life Sciences Institute, The University of Michigan, Ann Arbor, MI 48109, USA3 College of Pharmacy, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA4 Department of Molecular Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA5 Department of Pathology, The University of Michigan, Ann Arbor, MI 48109, USA6 Department of Biological Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA |
| |
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. |
| |
Keywords: | CNS, central nervous system NBD, nucleotide-binding domain SBD, substrate-binding domain MD, molecular dynamics TROSY, transverse relaxation optimized spectroscopy PDB, Protein Data Bank EDTA, ethylenediaminetetraacetic acid AMP-PNP, adenylyl-imidodiphosphate |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|