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Hsp70 Protein Complexes as Drug Targets

Victoria A. Assimon, Anne T. Gillies, Jennifer N. Rauch, Jason E. Gestwicki
2013 Current pharmaceutical design  
Thus, a promising strategy may be to block protein-protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts.  ...  Class A consists of an N-terminal J domain, a glycine-phenylalanine (G/F) rich region, a zinc finger-like region (ZFLR), a barrel topology C-terminal domain (CTD) and a dimerization domain [68, 69] .  ...  (A) Hsp70 is composed of a 45 kDa N-terminal nucleotide binding domain (NBD) connected to a 25 kDa substrate binding domain (SBD) by a short hydrophobic linker.  ... 
doi:10.2174/138161213804143699 pmid:22920901 pmcid:PMC3593251 fatcat:7e56flnxe5e4pc3trcul3kfwzy

Predicting protein targets for drug-like compounds using transcriptomics [article]

Nicolas A Pabon, Yan Xia, Samuel K. Estabrooks, Zhaofeng Ye, Amanda K. Herbrand, Evelyn Sub, Ricardo M. Biondi, Victoria A. Assimon, Jason E. Gestwicki, Jeffrey L. Brodsky, Carlos J. Camacho, Ziv Bar-Joseph
2018 bioRxiv   pre-print
To change this paradigm, we validated a new pipeline capable of identifying compound-protein interactions even for compounds with no similarity to known drugs.  ...  We further predicted targets for 1680 compounds and validated a total of seven novel interactions with four difficult targets, including non-covalent modulators of HRAS and KRAS.  ...  Since the ability to consider the cellular context is one of the major advantages of our method we added a feature to denote the impact a drug has on a cell line.  ... 
doi:10.1101/254367 fatcat:52ovirk3j5cflg54c4z6lcrsau

Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy

Zapporah T. Young, Jennifer N. Rauch, Victoria A. Assimon, Umesh K. Jinwal, Misol Ahn, Xiaokai Li, Bryan M. Dunyak, Atta Ahmad, George A. Carlson, Sharan R. Srinivasan, Erik R.P. Zuiderweg, Chad A. Dickey (+1 others)
2016 Cell Chemical Biology  
Here, we use a combination of chemical biology and genetics strategies to systematically perturb the affinity of Hsp70 for the model client, tau.  ...  Heat shock protein 70 (Hsp70) is a chaperone that normally scans the proteome and initiates the turnover of some proteins (termed "clients") by linking them to the degradation pathways.  ...  In these studies, used a combination of Hsc70, a J protein (DnaJA2) and a nucleotide-exchange factor (BAG-1).  ... 
doi:10.1016/j.chembiol.2016.04.014 pmid:27499529 pmcid:PMC4992411 fatcat:7ahgfxswwffdvet3tr346xy5a4

The E3 Ubiquitin Ligase CHIP and the Molecular Chaperone Hsc70 Form a Dynamic, Tethered Complex

Matthew C. Smith, K. Matthew Scaglione, Victoria A. Assimon, Srikanth Patury, Andrea D. Thompson, Chad A. Dickey, Daniel R. Southworth, Henry L. Paulson, Jason E. Gestwicki, Erik R. P. Zuiderweg
2013 Biochemistry  
with a wide range of clients.  ...  The E3 ubiquitin ligase CHIP (C-terminus of Hsc70 Interacting Protein, a 70 kDa homodimer) binds to the molecular chaperone Hsc70 (a 70 kDa monomer) and this complex is important in both the ubiquitination  ...  (a) A fluorophore-labelled probe binds to CHIP, but not Hsc70.  ... 
doi:10.1021/bi4009209 pmid:23865999 pmcid:PMC3856692 fatcat:z332xm4uwncn7ny2wnu3dwa64q

The Molecular Chaperone Hsp70 Activates Protein Phosphatase 5 (PP5) by Binding the Tetratricopeptide Repeat (TPR) Domain

Jamie N. Connarn, Victoria A. Assimon, Rebecca A. Reed, Eric Tse, Daniel R. Southworth, Erik R. P. Zuiderweg, Jason E. Gestwicki, Duxin Sun
2013 Journal of Biological Chemistry  
In this study, we find that both Hsp90 and Hsp70 bind to PP5 using a luciferase fragment complementation assay.  ...  We find that PP5 forms a stable 1:1 complex with Hsp70, but the interaction appears asymmetric with Hsp90, with one PP5 binding the dimer.  ...  A, schematic diagram of plasmid constructs.  ... 
doi:10.1074/jbc.m113.519421 pmid:24327656 pmcid:PMC3908423 fatcat:iai4lrlmx5gk3gdoyssagu6lmm

Predicting protein targets for drug-like compounds using transcriptomics

Nicolas A. Pabon, Yan Xia, Samuel K. Estabrooks, Zhaofeng Ye, Amanda K. Herbrand, Evelyn Süß, Ricardo M. Biondi, Victoria A. Assimon, Jason E. Gestwicki, Jeffrey L. Brodsky, Carlos J. Camacho, Ziv Bar-Joseph (+1 others)
2018 PLoS Computational Biology  
As a proof-of-principle for this regimen, top-10/top-100 target prediction accuracies of 26% and 41%, respectively, were achieved on a validation of set 152 FDA-approved drugs and 3104 potential targets  ...  To change this paradigm, we validated a new pipeline that identifies small molecule-protein interactions and works even for compounds lacking similarity to known drugs.  ...  a proteome-scale screen.  ... 
doi:10.1371/journal.pcbi.1006651 pmid:30532261 pmcid:PMC6300300 fatcat:r56vl7x3tjcerpebjdxfft3nze

Specific Binding of Tetratricopeptide Repeat Proteins to Heat Shock Protein 70 (Hsp70) and Heat Shock Protein 90 (Hsp90) Is Regulated by Affinity and Phosphorylation

Victoria A. Assimon, Daniel R. Southworth, Jason E. Gestwicki
2015 Biochemistry  
Assimon et al.  ...  In this study, we used a fluorescence polarization (FP) platform to systematically compare the affinities of five different human TPR co-chaperones Assimon et al.  ...  The column was then washed a third time with buffer A and then eluted in buffer A containing 3 mM ATP. The pure protein was concentrated and exchanged into buffer A for storage.  ... 
doi:10.1021/acs.biochem.5b00801 pmid:26565746 pmcid:PMC4714923 fatcat:j5ygy5tve5aktkzecizmjnjrua

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Sarah N. Fontaine, Mackenzie D. Martin, Elias Akoury, Victoria A. Assimon, Sergiy Borysov, Bryce A. Nordhues, Jonathan J. Sabbagh, Matt Cockman, Jason E. Gestwicki, Markus Zweckstetter, Chad A. Dickey
2015 Human Molecular Genetics  
The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)associated protein that functions to maintain MT stability, is implicated in a number of hereditary  ...  Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target.  ...  Acknowledgements This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans' Hospital.  ... 
doi:10.1093/hmg/ddv135 pmid:25882706 pmcid:PMC4560066 fatcat:ovoq2l323nevndbpnmsnwagp2e

A Local Allosteric Network in Heat Shock Protein 70 (Hsp70) Links Inhibitor Binding to Enzyme Activity and Distal Protein–Protein Interactions

Silvia Rinaldi, Victoria A. Assimon, Zapporah T. Young, Giulia Morra, Hao Shao, Isabelle R. Taylor, Jason E. Gestwicki, Giorgio Colombo
2018 ACS Chemical Biology  
The anticancer compound, MKT-077, is known to bind a conserved site in members of the Hsp70 family, which favors the ADP-bound state and interferes with a protein-protein interaction (PPI) at long range  ...  Together, the results indicate that MKT-077 interacts with loop222 to favor a pseudo-ADP bound conformer of Hsp70's NBD, even when ATP is present.  ...  Acknowledgements Our work is supported by grants from the National Institutes of Health (NS059690) to J.E.G. and from AIRC (Associazione Italiana Ricerca sul Cancro) through Grant IG 20019 to G.C. and through a  ... 
doi:10.1021/acschembio.8b00712 pmid:30372610 pmcid:PMC6377810 fatcat:ctdqjkazgbg4vohzmii4qny3vi

Isoform-selective Genetic Inhibition of Constitutive Cytosolic Hsp70 Activity Promotes Client Tau Degradation Using an Altered Co-chaperone Complement

Sarah N. Fontaine, Jennifer N. Rauch, Bryce A. Nordhues, Victoria A. Assimon, Andrew R. Stothert, Umesh K. Jinwal, Jonathan J. Sabbagh, Lyra Chang, Stanley M. Stevens, Erik R. P. Zuiderweg, Jason E. Gestwicki, Chad A. Dickey
2015 Journal of Biological Chemistry  
This shift in Hsc70 function by a single point mutation was the result of a change in the chaperome associated with Hsc70 such that DN-Hsc70 associated more with Hsp90 and DnaJ proteins, whereas wild type  ...  Conclusion: DN-Hsc70 recruits a pro-degradation chaperome complement to the Tau-Hsc70 complex.  ...  Acknowledgments-This is the result of work supported with resources and the use of facilities at the James A. Haley Veterans' Hospital. We thank Dr. Byeong Cha for assistance with microscopy.  ... 
doi:10.1074/jbc.m115.637595 pmid:25864199 pmcid:PMC4505567 fatcat:xyjud2qgbjfzti544sg2acbpue

High-throughput screen for inhibitors of protein–protein interactions in a reconstituted heat shock protein 70 (Hsp70) complex

Isabelle R. Taylor, Bryan M. Dunyak, Tomoko Komiyama, Hao Shao, Xu Ran, Victoria A. Assimon, Chakrapani Kalyanaraman, Jennifer N. Rauch, Matthew P. Jacobson, Erik R. P. Zuiderweg, Jason E. Gestwicki
2018 Journal of Biological Chemistry  
As a model system, we chose heat shock protein 70 (Hsp70), which is an ATP-dependent molecular chaperone that interacts with co-chaperones, including DnaJA2 and BAG2.  ...  A total of thirty analogs were created using a previously described synthetic route that features a Hantzsch thiazole condensation (Figure 4a ) (23) .  ...  As an alternative, we pursued a biochemical approach that is intended to borrow some strengths of a physiological milieu, such as multiple binding partners, with the precision of a well-defined  ... 
doi:10.1074/jbc.ra117.001575 pmid:29414793 fatcat:5xnxzr72u5ayhbiwathxordefe

Tryptophan Scanning Mutagenesis as a Way to Mimic the Compound-Bound State and Probe the Selectivity of Allosteric Inhibitors in Cells

Isabelle R Taylor, Victoria A Assimon, Szu Yu Kuo, Slvia Rinaldi, xiaokai Li, Zapporah T Young, Giulia Morra, Keith Green, Daniel Nguyen, Hao Shao, Sylvie Garneau-Tsodikova, Giorgio Colombo (+1 others)
2020 Chemical Science  
Understanding the selectivity of a small molecule for its target(s) in cells is an important goal in chemical biology and drug discovery. One powerful way to address this question is...  ...  phenotype that is similar to expression of a dominant negative (DN), a variant of the target enzyme in which a key, catalytic residue is removed. 25 cause each of these methods has its own strengths,  ...  it oen takes more than one experiment (e.g. pulldowns combined with a DN) to ultimately conclude that a compound is sufficiently selective to be used as a chemical probe. 3, 4 However, achieving this  ... 
doi:10.1039/c9sc04284a pmid:34123282 pmcid:PMC8148087 fatcat:3rzrhszayzfwfmyc2fhismxpxe

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation

Sue-Ann Mok, Carlo Condello, Rebecca Freilich, Anne Gillies, Taylor Arhar, Javier Oroz, Harindranath Kadavath, Olivier Julien, Victoria A. Assimon, Jennifer N. Rauch, Bryan M. Dunyak, Jungsoon Lee (+5 others)
2018 Nature Structural & Molecular Biology  
Supplementary Figure 1 Supporting data for in vitro tau aggregation screen a) Addition of Hsc70 to tau prior to aggregation induction leads to dose-dependent effects on aggregation. 0N4R tau WT incubated  ...  Supplementary Figure 2 Data analysis of additional calculated kinetic parameters from tau aggregation screen a) Heatmap representing the effect of individual chaperones on the elongation rate constant  ... 
doi:10.1038/s41594-018-0057-1 pmid:29728653 fatcat:5uk73hc6cfhv5nhlwkopuk27eu

Analysis of the Arabinose-5-Phosphate Isomerase of Bacteroides fragilis Provides Insight into Regulation of Single-Domain Arabinose Phosphate Isomerases

D. Cech, P. F. Wang, T. P. Holler, R. W. Woodard
2014 Journal of Bacteriology  
Classical APIs, such as Escherichia coli KdsD, contain a sugar isomerase domain and a tandem cystathionine beta-synthase domain.  ...  These results suggest that Q5LIW1 may be a suitable system to study API structure-function relationships.  ...  We thank Andrew Pratt for his helpful discussions and review of the manuscript, Kyle Heslip for the use of the Dotson lab plate reader, Victoria Assimon for the original cloning of the BF0137 gene, Ted  ... 
doi:10.1128/jb.01735-14 pmid:24891442 pmcid:PMC4135666 fatcat:rhsrhe4sj5caxo7qcvsoj6w4sm

Switchable assembly and function of antibody complexes in vivo using a small molecule

Alexander J. Martinko, Erin F. Simonds, Suchitra Prasad, Alberto Ponce, Colton J. Bracken, Junnian Wei, Yung-Hua Wang, Tiffany-Lynn Chow, Zhong Huang, Michael J. Evans, James A. Wells, Zachary B. Hill
2022 Proceedings of the National Academy of Sciences of the United States of America  
of a cytokine's half-life, and activation of bispecific, T cell–engaging antibodies.  ...  The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics.  ...  We thank Victoria Assimon for useful input on figure aesthetics.  ... 
doi:10.1073/pnas.2117402119 pmid:35210365 pmcid:PMC8892515 fatcat:nmx25u2tonatbloewg6afyznda
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