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A biophysical study of protein dynam...

Pearson, Joshua Thomas.

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A biophysical study of protein dynamics and protein-ligand interactions.

Record Type:	Electronic resources : Monograph/item
Title/Author:	A biophysical study of protein dynamics and protein-ligand interactions./
Author:	Pearson, Joshua Thomas.
Description:	129 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0904.
Contained By:	Dissertation Abstracts International67-02B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3205875
ISBN:	9780542544286

A biophysical study of protein dynamics and protein-ligand interactions.
Pearson, Joshua Thomas.

A biophysical study of protein dynamics and protein-ligand interactions. - 129 p.

Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0904.

Thesis (Ph.D.)--University of Washington, 2006.

The focus of this work is the application of various biophysical techniques for the study of protein dynamics and protein-ligand interactions. The first three chapters of this work concern the characterization of bacterial glutamine synthetase (GS) by fluorescence spectroscopy and protein mass spectrometry. As described in the introduction to glutamine synthetases (Chapter 1), these enzymes exist as a dodecamer, two hexameric rings stacked face-to-face. Protruding into the central cavity of this supramolecular ring structure is the 'central loop'. This 'central loop' has been shown to be essential for enzyme function. Chapter 2 describes our characterization of the conformational dynamics and function of the central loop of E. coli GS. GS has emerged as a potential pharmacological target for tuberculosis therapy and is known to be a highly regulated enzyme, with adenylylation decreasing enzymatic activity. Chapter 3 describes our utilization of mass spectrometry to characterize the adenylylation process of Mycobacterium tuberculosis GS. Chapters 4 and 5 describe our utilization of surface plasmon resonance (SPR) to monitor antifungal azole drugs to cytochrome P4503A4 (CYP3A4). CYP3A4 is known to exhibit non-hyperbolic kinetics, where binding of multiple ligands to the enzyme alters its kinetics. Substrates are also known to be oxidized to various products, suggesting that a single substrate or ligand, can adopt multiple conformations while bound to the enzyme. Through SPR, we are able to directly observe two binding orientations for the antifungal drugs itraconazole and ketoconazole within the active site of CYP3A4. These results demonstrate the utility of SPR to elucidate complex ligand-protein interactions.

ISBN: 9780542544286Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

A biophysical study of protein dynamics and protein-ligand interactions.
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520 $a The focus of this work is the application of various biophysical techniques for the study of protein dynamics and protein-ligand interactions. The first three chapters of this work concern the characterization of bacterial glutamine synthetase (GS) by fluorescence spectroscopy and protein mass spectrometry. As described in the introduction to glutamine synthetases (Chapter 1), these enzymes exist as a dodecamer, two hexameric rings stacked face-to-face. Protruding into the central cavity of this supramolecular ring structure is the 'central loop'. This 'central loop' has been shown to be essential for enzyme function. Chapter 2 describes our characterization of the conformational dynamics and function of the central loop of E. coli GS. GS has emerged as a potential pharmacological target for tuberculosis therapy and is known to be a highly regulated enzyme, with adenylylation decreasing enzymatic activity. Chapter 3 describes our utilization of mass spectrometry to characterize the adenylylation process of Mycobacterium tuberculosis GS. Chapters 4 and 5 describe our utilization of surface plasmon resonance (SPR) to monitor antifungal azole drugs to cytochrome P4503A4 (CYP3A4). CYP3A4 is known to exhibit non-hyperbolic kinetics, where binding of multiple ligands to the enzyme alters its kinetics. Substrates are also known to be oxidized to various products, suggesting that a single substrate or ligand, can adopt multiple conformations while bound to the enzyme. Through SPR, we are able to directly observe two binding orientations for the antifungal drugs itraconazole and ketoconazole within the active site of CYP3A4. These results demonstrate the utility of SPR to elucidate complex ligand-protein interactions.
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