| dc.identifier.uri | http://hdl.handle.net/11401/76478 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Protein kinases, as key cellular pathway regulators, are known drivers of cancer and have been successfully targeted with drugs to treat patients with certain types of cancers. However, the high sequence and structural conservation of the active site found in the multitude of protein kinases has created a challenge to developing specific inhibitors, which are necessary to prevent side effects caused by off target inhibition. Part of the mechanism through which protein kinases achieve precise regulation involves integration of many inter- and intramolecular signals via sites on the kinase that are considerably less well conserved in sequence and function. These sites therefore provide the opportunity for more specific therapeutic targeting, for example, through the development of allosteric inhibitors. However, it is challenging to identify such allosteric sites. The first part of my work identified an allosteric network of dynamically coupled amino acids in Src kinase that connects regulatory sites to the ATP- and substrate-binding sites. This work provides new insights into the regulation of protein tyrosine kinases and establishes a potential conduit by which resistance mutations to ATP-competitive kinase inhibitors can affect their activity. Secondly, I examined a site at the end of this allosteric network that was also identified by recent computational studies as a potential ligand binding site. By identifying a ligand that specifically binds to this allosteric site, I have provided a proof of principle that it is possible to predict allosteric binding sites and their ligands in the kinase domain, providing a route towards development of novel cancer therapeutics. Finally, I focused on another important enzyme whose targeting could lead to important future treatment options, Insulin Degrading Enzyme (IDE). Despite the identification of IDE as a diabetes susceptibility gene, the relationship between the activity of the protease IDE and glucose homeostasis remains unclear. My work explored the structural details of a newly discovered, physiologically active, IDE inhibitor identified from a DNA-templated macrocycle library. This inhibitor, which engages a binding pocket away from the catalytic site, demonstrates the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes. These three examples provide a better understanding on how targeting disease relevant enzyme at distal sites could provide future breakthrough treatments. | |
| dcterms.available | 2017-09-20T16:50:22Z | |
| dcterms.contributor | Seeliger, Markus A | en_US |
| dcterms.contributor | Miller, W. Todd | en_US |
| dcterms.contributor | Lin, Richard | en_US |
| dcterms.contributor | Bowen, Mark | en_US |
| dcterms.contributor | Rizzo, Robert. | en_US |
| dcterms.creator | Foda, Zachariah Hussein | |
| dcterms.dateAccepted | 2017-09-20T16:50:22Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:22Z | |
| dcterms.description | Department of Molecular and Cellular Biology. | en_US |
| dcterms.extent | 195 pg. | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | http://hdl.handle.net/11401/76478 | |
| dcterms.issued | 2015-05-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:22Z (GMT). No. of bitstreams: 1
Foda_grad.sunysb_0771E_12288.pdf: 20901719 bytes, checksum: 2b23878dec5d324d9a4f43d486259016 (MD5)
Previous issue date: 2015 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Allostery, Cooperativity, High throughput screening, Insulin Degrading Enzyme, Src Kinase | |
| dcterms.subject | Biochemistry | |
| dcterms.title | Structural studies on allosteric regulation and drug binding | |
| dcterms.type | Dissertation | |
