George, Kelly
(2019)
EXPANDING THE SCOPE OF HETEROGENEOUS BACKBONE DESIGNS TO INCLUDE SINGLE- AND MULTI-DOMAIN ZINC FINGER PROTEINS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Polymers with specific folded conformations — termed “foldamers” — lend themselves to a range of potential applications in therapeutic development and biomedical and material sciences. One promising approach to foldamer design is to incorporate a combination of unnatural building blocks that retain a peptide’s natural side chains while altering the backbone upon which the side chains are displayed. This creates a peptide variant with a heterogenous backbone and native-like folds and functions.
The focus of this dissertation is on recent work towards expanding the scope of heterogeneous backbone design strategies and consists of two main goals. The first goal is to mimic the tertiary structure of a single zinc finger domain (the third finger of Specificity protein 1, Sp1-3). This expands design strategies past simple tertiary structures and presents dynamic challenges such as retaining a precise metal coordination site. Data shown here indicate that appropriately designed alterations can allow for a tertiary structure that is superior to that of the native backbone in the context of folded stability and native ligand binding.
The second goal discussed in this work is two part: 1) to investigate if the increase in folded stability seen with single domain Sp1-3 backbone variants can be generalized to other Cis2His2 zinc finger sequences and 2) to synthesize a multi-domain zinc finger protein through native chemical ligation. Each of these aims attempts to push towards the longer-term goal of gaining a better understanding of how backbone alterations impact DNA binding in multi-domain zinc fingers.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
30 January 2019 |
| Date Type: |
Publication |
| Defense Date: |
31 August 2018 |
| Approval Date: |
30 January 2019 |
| Submission Date: |
18 August 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
113 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
foldamers, unnatural peptides, peptide therapeutics |
| Date Deposited: |
30 Jan 2019 22:47 |
| Last Modified: |
30 Jan 2019 22:47 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35473 |
Available Versions of this Item
-
EXPANDING THE SCOPE OF HETEROGENEOUS BACKBONE DESIGNS TO INCLUDE SINGLE- AND MULTI-DOMAIN ZINC FINGER PROTEINS. (deposited 30 Jan 2019 22:47)
[Currently Displayed]
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}