Hsp70 (heat shock 70 kDa) chaperone proteins are central to protein folding, refolding, and trafficking in organisms ranging from Archae to Homo Sapiens, both at normal and at stressed cellular conditions. Hsp70's (re) fold proteins via binding and release cycles at the substrate-binding domain involving conformational changes caused by ATP and ADP binding at the nucleotide-binding domain. This remote regulation mechanism is called allostery. Recently, Hsp70's have been linked to diseases such as breast cancer. Modulation of the allosteric mechanism of the Hsp70's with small compounds may form an avenue to treat these diseases. We propose to investigate the mechanism in detail by determining the solution conformations of 60 kDa Hsp70 protein constructs, containing both nucleotide- and substrate-binding domains and their complexes with co-chaperones in different liganded states. We will investigate the molecular basis for the action of the first generation of Hsp70 modulating compounds. The combined insights gained will aid in the design of improved compounds for the treatment of cell-management diseases. The research will be carried out using ultra-high field nuclear magnetic resonance spectroscopy.
| Zuiderweg, Erik R P; Bertelsen, Eric B; Rousaki, Aikaterini et al. (2013) Allostery in the Hsp70 chaperone proteins. Top Curr Chem 328:99-153 |
| Rousaki, Aikaterini; Miyata, Yoshinari; Jinwal, Umesh K et al. (2011) Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J Mol Biol 411:614-32 |
| Bagai, Ireena; Ragsdale, Stephen W; Zuiderweg, Erik R P (2011) Pseudo-4D triple resonance experiments to resolve HN overlap in the backbone assignment of unfolded proteins. J Biomol NMR 49:69-74 |
| Ahmad, Atta; Bhattacharya, Akash; McDonald, Ramsay A et al. (2011) Heat shock protein 70 kDa chaperone/DnaJ cochaperone complex employs an unusual dynamic interface. Proc Natl Acad Sci U S A 108:18966-71 |
| Bhattacharya, Akash; Revington, Matthew; Zuiderweg, Erik R P (2010) Measurement and interpretation of 15N-1H residual dipolar couplings in larger proteins. J Magn Reson 203:11-28 |
| Crippen, Gordon M; Rousaki, Aikaterini; Revington, Matthew et al. (2010) SAGA: rapid automatic mainchain NMR assignment for large proteins. J Biomol NMR 46:281-98 |
| Wisén, Susanne; Bertelsen, Eric B; Thompson, Andrea D et al. (2010) Binding of a small molecule at a protein-protein interface regulates the chaperone activity of hsp70-hsp40. ACS Chem Biol 5:611-22 |
| Bertelsen, Eric B; Chang, Lyra; Gestwicki, Jason E et al. (2009) Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proc Natl Acad Sci U S A 106:8471-6 |
| Bhattacharya, Akash; Kurochkin, Alexander V; Yip, Grover N B et al. (2009) Allostery in Hsp70 chaperones is transduced by subdomain rotations. J Mol Biol 388:475-90 |
| Weaver, Daniel S; Zuiderweg, Erik R P (2009) Protein proton-proton dynamics from amide proton spin flip rates. J Biomol NMR 45:99-119 |
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