Full metadata
Title
Structural Based Drug Discovery: The Significance of Protein Structure
Description
Structural-based drug discovery is becoming the essential tool for drug development withlower cost and higher efficiency compared to the conventional method. Knowledge of the
three-dimensional structure of protein targets has the potential to accelerate the process
for screening drug candidates. X-ray crystallography has proven to be the most used and
indispensable technology in structural-based drug discovery. The provided
comprehensive structural information about the interaction between the disease-related
protein target and ligand can guide the chemical modification on the ligand to improve
potency and selectivity. X-ray crystallography has been upgraded from traditional
synchrotron to the third generation, which enabled the surge of the structural
determination of macromolecular. The introduction of X-ray free electron laser further
alleviated the uncertain and time-consuming crystal size optimization process and
extenuated the radiation damage by “diffraction before destruction”. EV-D68 2A
protease was proved to be an important pharmaceutical target for acute flaccid myelitis.
This thesis reports the first atomic structure of the EV-D68 2A protease and the structuresof its two mutants, revealing it adopting N-terminal four-stranded sheets and C-terminal
six-stranded ß-barrels structure, with a tightly bound zinc atom. These structures will
guide the chemical modification on its inhibitor, Telaprevir. Integrin ⍺Mβ2 is an integrin
with the α I-domain, related to many immunological functions including cell
extravasation, phagocytosis, and immune synapse formation, so studying the molecular
ligand-binding mechanism and activation mechanism of ⍺Mβ2 is of importance. This
thesis uncovers the preliminary crystallization condition of ⍺Mβ2-I domain in complex
with its ligand Pleiotrophin and the initial structural model. The structural model shows consistency with the previous hypothesis that the primary binding sites are metal iondependent
adhesion sites on ⍺Mβ2-I domain and the thrombospondin type-1 repeat (TSR)
domains of Pleiotrophin. Drug molecules with high potency and selectivity can be
designed based on the reported structures of the EV-D68 2A protease and ⍺Mβ2-I domain
in the future.
Date Created
2021
Contributors
- Liu, Chang (Author)
- Liu, Wei (Thesis advisor)
- Stephanopoulos, Nicholas (Committee member)
- Chiu, Po-Lin (Committee member)
- Arizona State University (Publisher)
Topical Subject
Resource Type
Extent
138 pages
Language
eng
Copyright Statement
In Copyright
Primary Member of
Peer-reviewed
No
Open Access
No
Handle
https://hdl.handle.net/2286/R.2.N.168308
Level of coding
minimal
Cataloging Standards
Note
Partial requirement for: Ph.D., Arizona State University, 2021
Field of study: Biochemistry
System Created
- 2022-08-22 02:02:13
System Modified
- 2022-08-22 02:02:38
- 2 years 2 months ago
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