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Solution NMR studies of HIV-1 reverse transcriptase

Sharaf, Naima (2017) Solution NMR studies of HIV-1 reverse transcriptase. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The human immunodeficiency virus (HIV-1) is a well-recognized threat to global public health,
with current estimates of ~37 million infected individuals worldwide [1]. While efforts to
develop an effective vaccine to prevent infection have not come to fruition, several FDA
approved drugs targeting HIV-1 have proven effective in reducing viral replication and
improving quality of life [2]. Yet, due to the increasing emergence of drug resistant variants, new
HIV-1 treatments are needed as the virus continues to evolve. Structure-based drug design is a
powerful approach for facilitating the development of new HIV-1 inhibitors [3], driven mainly
by x-ray crystallographic studies of viral proteins [4]. However, the static nature of
crystallographic studies necessitate complementary structural and dynamic studies to genuinely
understand protein-ligand interactions. In this thesis, solution NMR is used to investigate HIV-1
RT, a major therapeutic target in the fight against HIV-1 infection. HIV-1 reverse transcriptase
produces viral DNA from genomic RNA and is essential for the viral lifecycle [5]. Although the
structure of the mature heterodimer has been well characterized, less is known about RT
maturation from its p66 immature precursor, which so far has resisted crystallization. I used
NMR to investigate RT maturation and to elucidate RT interactions with FDA approved
inhibitors. Together the results of my thesis contribute to arrive at a more comprehensive
understanding of RT maturation and RT-inhibitor interactions.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sharaf, Naimangs10@pitt.edu0000-0002-3662-9228
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGronenborn, Angela
Committee Membervan der Wel, Patrick
Committee MemberIshima, Rieko
Committee MemberMontelaro, Ronald
Date: 6 January 2017
Date Type: Publication
Defense Date: 21 November 2016
Approval Date: 6 January 2017
Submission Date: 9 December 2016
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 107
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Biophysics and Structural Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Fluorine NMR, HIV-1 reverse transcriptase
Date Deposited: 06 Jan 2017 15:57
Last Modified: 07 Jan 2017 06:15

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