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Dimerization of the SARS coronavirus...

The Johns Hopkins University.

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Dimerization of the SARS coronavirus 3CL protease is controlled through long-range interactions.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Dimerization of the SARS coronavirus 3CL protease is controlled through long-range interactions./
Author:	Barrila, Jennifer Ann.
Description:	195 p.
Notes:	Adviser: Ernesto Freire.
Contained By:	Dissertation Abstracts International69-12B.
Subject:	Biophysics, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3339678
ISBN:	9780549936282

Dimerization of the SARS coronavirus 3CL protease is controlled through long-range interactions.
Barrila, Jennifer Ann.

Dimerization of the SARS coronavirus 3CL protease is controlled through long-range interactions. - 195 p.

Adviser: Ernesto Freire.

Thesis (Ph.D.)--The Johns Hopkins University, 2009.

Coronaviruses are important human and veterinary pathogens. Traditionally, these viruses are known to produce mild respiratory infections in humans with more fatal infections occurring in livestock and other animals. This view changed in late 2002 with the emergence of a dangerous human coronavirus known as the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). The development of broad-spectrum antivirals is focused on the main viral protease, 3CL pro, a conserved target in all known coronaviruses. Since the enzyme is a homodimer and the individual monomers are inactive, two approaches are being used to develop inhibitors: enzyme inhibitors that target the active site and dimerization inhibitors. Both of these approaches are discussed in this thesis. We previously identified class of substrate-analog inhibitors which effectively target SARS 3CLpro. In order to characterize the mode of binding of these compounds, a crystallographic structure of SARS 3CLpro in complex with Compound 4 was determined at a 2.7 A resolution. The structure sheds light on the mode of inhibitor binding for Compound 4 and provides a starting point for the structure-based optimization. The key mechanisms involved in the dimerization of the protease must be determined when considering the second approach to drug design against 3CLpro . The ultimate aim of this thesis is to identify these underlying mechanisms in order to propose novel strategies for designing small molecule inhibitors against the protease. It is demonstrated using mutational analysis that the dimerization of SARS 3CLpro is controlled not only by direct interactions localized to the dimer interface, but also through long-range interactions as well. In particular, the mutation of residues Ser147 and Asn28, which do not make any contact with the opposing subunit and are located greater than 9 A away from the dimer interface, resulted in a complete loss of enzymatic activity and interfered with dimerization. A crystallographic structure of the N28A mutant at a 2.35 A resolution provides a structural basis for the loss observed in dimerization and activity. The finding that residues away from the dimer interface are able to control dimerization defines alternative subsites for the design of dimerization inhibitors.

ISBN: 9780549936282Subjects--Topical Terms:

1019105
Biophysics, General.

Dimerization of the SARS coronavirus 3CL protease is controlled through long-range interactions.
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245 1 0 $a Dimerization of the SARS coronavirus 3CL protease is controlled through long-range interactions.
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502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2009.
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