Hsp70 chaperone Proteins and their Interactions with Various Drugs as Studied by Nuclear Magnetic Resonance.

Rousaki, Aikaterini

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dc.contributor	Al-Hashimi, Hashim M.
dc.contributor	Zuiderweg, Erik R P
dc.contributor	Carlson, Heather A.
dc.contributor	Gestwicki, Jason E.
dc.contributor	Xu, Zhaohui
dc.creator	Rousaki, Aikaterini
dc.date	2011-09-15T17:18:11Z
dc.date	NO_RESTRICTION
dc.date	2011-09-15T17:18:11Z
dc.date	2011
dc.date
dc.date.accessioned	2022-05-19T10:49:17Z
dc.date.available	2022-05-19T10:49:17Z
dc.identifier	https://hdl.handle.net/2027.42/86521
dc.identifier.uri	http://localhost:8080/xmlui/handle/CUHPOERS/101737
dc.description	Chaperone proteins and their cochaperones are perhaps one of the most intriguing systems for investigation. Ubiquitous in nature, they can be found in every organism and that perhaps is the reason that their sequence shows amazingly high homology and similarity. Allosteric mechanisms govern their functions and that makes them very interesting and hard to investigate at the same time. In medicine, chaperone proteins are of extreme interest since they are related to various diseases including neurodegerative diseases such as Alzheimers disease, Pick’s disease and Parkinsons disease. Various forms of cancer also relate to the chaperone proteins. Hence the investigation of various small molecules that could up/down-regulate this system is of great biomedical relevance. In this dissertation we explored a member of the chaperone family that is constitutively expressed in every mammalian cell, the cognate Hsp70 (Hsc70). More specifically, we investigate the interactions of its ATPase domain with various small molecules that either act as inhibitors or enhancers of the protein’s activity. For example, we found that the compound MKT-077 blocks the Hsc70 ATPase activity by binding in a negatively charged cleft with its positive charge. This was identified with the use of chemical shift mapping experiments, NOE experiments and AUTODOCK simulations. MKT-077 binds only to the ADP form of the protein elucidating an amazing mechanism for the inhibition of the protein. Another inhibitor, methylene blue, binds to another locus of the ATPase. Interestingly, both of these molecules reduce the levels of tau in cell-based models of Alzheimers disease. This would suggest that the use of compounds that bind to Hsc70 at two separate sites could modulate Hsp70 activity in cells in a synergistic fashion.
dc.description	Ph.D.
dc.description	Biophysics
dc.description	University of Michigan, Horace H. Rackham School of Graduate Studies
dc.description	http://deepblue.lib.umich.edu/bitstream/2027.42/86521/1/rousaki_1.pdf
dc.format	application/pdf
dc.language	en_US
dc.subject	NMR
dc.subject	Protein
dc.subject	Drug
dc.subject	Small Molecule
dc.subject	Ligand
dc.subject	Chaperone
dc.subject	Biomedical Engineering
dc.subject	Chemical Engineering
dc.subject	Computer Science
dc.subject	Engineering (General)
dc.subject	Materials Science and Engineering
dc.subject	Nuclear Engineering and Radiological Sciences
dc.subject	Biological Chemistry
dc.subject	Complementary and Alternative Medicine
dc.subject	Dentistry
dc.subject	Genetics
dc.subject	Medicine (General)
dc.subject	Microbiology and Immunology
dc.subject	Molecular, Cellular and Developmental Biology
dc.subject	Neurosciences
dc.subject	Pathology
dc.subject	Pharmacy and Pharmacology
dc.subject	Physical Medicine and Rehabilitation
dc.subject	Public Health
dc.subject	Chemistry
dc.subject	Ecology and Evolutionary Biology
dc.subject	Mathematics
dc.subject	Natural Resources and Environment
dc.subject	Physics
dc.subject	Science (General)
dc.subject	Statistics and Numeric Data
dc.subject	Engineering
dc.subject	Health Sciences
dc.subject	Science
dc.title	Hsp70 chaperone Proteins and their Interactions with Various Drugs as Studied by Nuclear Magnetic Resonance.
dc.type	Thesis