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Interactions of Cytochrome P450 3A4 with Phospholipid Bilayer Nanodiscs
Cytochrome P450s (CYPs) are the major drug-metabolizing enzyme in humans. Cytochrome P450 3A4 (CYP3A4), in particular, is responsible for approximately half of all CYP-mediated drug metabolism. In mammals, drug-metabolizing CYPs are membrane proteins, and molecular dynamics simulations have been performed by several groups ...
Structural Insights into Viral Membrane Fusion Machinery via Cryo-Electron Tomography: Influenza Virus and Human Parainfluenza Virus
Enveloped viruses such as influenza virus and human parainfluenza virus utilize specialized protein machinery to fuse their membrane with the cellular membrane of target host cells and thus deliver their genome for replication. This protein-mediated membrane fusion is also a ubiquitous and key event that underlies many ...
Biophysical and Structural Approaches to Characterize the Mechanism of P-glycoprotein, a Multidrug Efflux Transporter
P-glycoprotein (P-gp), an ATP Binding Cassette transporter (ABCB1), plays an important role in multidrug resistance in cancers and clinical drug interactions. P-gp utilizes the energy from ATP hydrolysis to drive conformational transitions from the inward-facing (IF) to outward-facing (OF) states that lead to extracellular ...
Controlled Assembly of Viral Surface Proteins into Biological Nanoparticles
(2014-02-24)
In recent years, therapeutic use of engineered particles on the 1-1,000 nm scale has gained popularity; these nanoparticles have been developed for use in drug delivery, gene therapy, vaccine preparation, and diagnostics. Often, viral proteins are utilized in the design of such species, and outlined here are completed studies ...
Decoding the Structural Determinants of Hemagglutinin Mediated Influenza Entry and Antigenicity
The fusion glycoproteins found on the surface of enveloped viruses enable the delivery of the viral genome into the host cell by facilitating the merger of the viral membrane with the host cell membrane, an essential step for a productive infection. The thermodynamically favorable but kinetically slow process of spontaneous ...
A Biophysical Rationalization of Type II and Reverse Type I Inhibitor Interactions in CYP450 with Implications for Enzyme Function
(2013-11-14)
This work is a characterization of small molecule azole-based inhibitor interactions in cytochrome P450 (CYP) using a complement of biophysical methodologies to provide molecular level details of the underappreciated structural complexity of low-spin (Type II and associated reverse Type I) CYP-ligand complexes. Specifically, ...
Conformational Heterogeneity and Catalytic Promiscuity in Glutathione Transferases
(2013-02-25)
Enzymological paradigms have shifted recently to acknowledge the biological importance of catalytic promiscuity. Detoxification enzymes, such as glutathione transferases, are known to be highly promiscuous. One common suggestion is that promiscuous enzymes are more conformationally heterogeneous than their substrate-specific ...
Cooperative Assembly of Terminase and Integration Host Factor at the Packaging Initiation Site of Bacteriophage Lambda
(2013-11-14)
Packaging of viral genomes into procapsids by terminase enzymes is conserved in many DNA viruses. Terminases bind to linear concatemers of replicated viral genomes and concomitantly excise (mature) and package a single genome per procapsid. In this thesis, I interrogate the role of E. coli integration host factor (IHF) in ...
Biophysical Approaches for the Development of Stable, Long-Lived, Multi-Functional, and Potent Antibody Therapeutics
Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors, but they have also proven extremely amenable ...
Mechanisms of antibody-mediated neutralization targeting viral glycoproteins
The antibody response against viral glycoproteins is important for preventing many viral infections but we lack a comprehensive understanding of the mechanisms by which antibodies act. Furthermore, the immense antigenic variability of glycoproteins complicates the design of immunogens that must elicit broadly neutralizing ...