| dc.identifier.uri | http://hdl.handle.net/11401/77608 | |
| 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 tyrosine phosphatase 1B (PTP1B) is an important negative regulator of signaling by the insulin and leptin receptors. PTP1B-null mice are sensitized to insulin and resistant to diet-induced obesity, making PTP1B a prized target in the pharmaceutical industry for therapeutic intervention in type two diabetes and obesity. Efforts to develop inhibitors of PTP1B focused on the active site pocket; however, those efforts have been hindered by poor oral bioavailability of the compounds. Our lab has exploited the conformational changes associated with redox regulation of PTP1B to devise an alternative method of inhibiting the enzyme. Reactive oxygen species, generated in response to insulin receptor tyrosine kinase signaling, oxidize the thiol of the catalytic cysteine, temporarily inactivating PTP1B. Reversible oxidation of PTP1B (oxPTP1B) results in a profound conformational change at the catalytic site. We have identified by phage display a single chain variable fragment antibody (scFv45) that selectively binds oxPTP1B and stabilizes it. When expressed in cells, scFv45 leads to potentiation of insulin signaling. We have pursued molecular and structural studies to determine the basis for the interaction between scFv45 and oxPTP1B. By comparison with T-cell protein tyrosine phosphatase (TCPTP), with which it shares 74% sequence identity in the catalytic domain, we have found that a combination of both residue identity and conformational changes confer specificity to the binding interaction between scFv45 and oxPTP1B. These data suggest a strategy for development of small molecule inhibitors that mimic the effects of scFv45. This study is discussed in the context of identification of chelerythrine as a small molecule mimic of scFv45 and inhibitor of PTP1B function. Overall our data reveal a path to identification of therapeutic molecules that sensitize insulin signaling in type 2 diabetes and obesity by selectively inhibiting that pool of PTP1B that regulates insulin and leptin signaling. | |
| dcterms.available | 2017-09-20T16:52:59Z | |
| dcterms.contributor | Tonks, Nicholas K | en_US |
| dcterms.contributor | Girnun, Geoffrey | en_US |
| dcterms.contributor | Seeliger, Markus | en_US |
| dcterms.contributor | Lin, Richard | en_US |
| dcterms.contributor | Joshua-Tor, Leemor | en_US |
| dcterms.contributor | Bennett, Anton . | en_US |
| dcterms.creator | Rus, Ioana Rus | |
| dcterms.dateAccepted | 2017-09-20T16:52:59Z | |
| dcterms.dateSubmitted | 2017-09-20T16:52:59Z | |
| dcterms.description | Department of Genetics | en_US |
| dcterms.extent | 120 pg. | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | http://hdl.handle.net/11401/77608 | |
| dcterms.issued | 2016-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:52:59Z (GMT). No. of bitstreams: 1
Rus_grad.sunysb_0771E_12865.pdf: 40264915 bytes, checksum: 6d71277eeb7cd95c232315a705847f80 (MD5)
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Biology | |
| dcterms.subject | diabetes, obesity, PTP1B, scFv45 | |
| dcterms.title | Harnessing Redox Regulation of PTP1B: a Novel Path to Therapeutic Design | |
| dcterms.type | Dissertation | |
