SRIRAM, SHASHI KANTH
(2012)
THE N-END RULE PATHWAY: MOLECULAR PRINCIPLES OF STRUCTURAL RECOGNITION AND RATIONAL DESIGN OPPORTUNITIES.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The N-end rule relates the regulation of the in vivo half-life of a protein to the identity of its N-terminal residue. A set of N-terminal degradation signals is targeted by the recognition components (N-recognins) of the N-end rule pathway. Recent reports on the N-end rule substrates, components, functions and structural basis of substrate recognition have provided critical insights. The N-end rule pathway is now emerging as a major ubiquitin-dependent cellular proteolytic system. The scope of this dissertation is to understand the structural principles of substrate recognition and utilize this structural basis to provide insights on the functions and underlying mechanisms of the N-end rule pathway. We were also interested in exploring the N-end rule pathway as an intracellular target for heterodivalent interactions. We discuss and demonstrate the basis of thermodynamics and kinetics principles that govern these interactions between the N-recognins and the heterodivalent ligands. We further pursued to exploit these principles in the design and development of high affinity ligands that target the N-end rule pathway.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| SRIRAM, SHASHI KANTH | SHS77@PITT.EDU | SHS77 | |
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| ETD Committee: |
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| Date: |
14 August 2012 |
| Date Type: |
Publication |
| Defense Date: |
18 April 2012 |
| Approval Date: |
14 August 2012 |
| Submission Date: |
13 August 2012 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
100 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
PROTEIN DEGRADATION, UBIQUITIN, N-END RULE PATHWAY, UBIQUITIN-PROTEASOME SYSTEM, UPS, UBR PROTEINS, UBR INHIBITORS, FRAGMENT-BASED DRUG DESIGN, FBDD, RATIONAL DESIGN, UBR STRUCTURE |
| Date Deposited: |
14 Aug 2012 11:00 |
| Last Modified: |
15 Nov 2016 14:01 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13540 |
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