The long range goal of this project is to study structure-function relationships in nitric oxide synthase (NOS). NOS is the enzyme responsible for the oxidation of arginine to nitric oxide (NO). In recent years, nitric oxide has been recognized as a major physiological messenger molecule involved in the nervous, immune, and cardiovascular systems. Owing to the potency and importance of NO as a regulatory molecule, NOS is a complex enzyme under stringent control. The enzyme consists of a heme domain, where the actual oxidation of arginine occurs and an FMN/FAD domain that serves to shuttle electrons from NADPH to the heme domain. Between the heme and flavin domains is a linker that binds another regulatory molecule, calmodulin. In addition to heme, FMN, and FAD, NOS contains yet another cofactor, tetrahydrobiopterin. Our lab has solved the crystal structure of the catalytic heme domain of all 3 mammalian NOS isoforms. This has opened the way for using structure-based approaches for developing isoform-selective selective inhibitors. A combination of crystallography, in vivo/in vitro testing, computational chemistry, and synthetic chemistry will be used to develop novel isoform-selective inhibitors. In addition, new technologies will be incorporated into the problem of NOS dynamics and electron transfer. In particular, is the use of high field NMR spectroscopy to study domain interactions in hoio-NOS and laser flash photolysis methods for studying electron transfer processes. ? ? ?
| Li, Huiying; Evenson, Ryan J; Chreifi, Georges et al. (2018) Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-carboximidamides. Biochemistry 57:6319-6325 |
| Batabyal, Dipanwita; Poulos, Thomas L (2018) Effect of redox partner binding on CYP101D1 conformational dynamics. J Inorg Biochem 183:179-183 |
| Tripathi, Sarvind; Poulos, Thomas L (2018) Testing the N-Terminal Velcro Model of CooA Carbon Monoxide Activation. Biochemistry 57:3059-3064 |
| Batabyal, Dipanwita; Richards, Logan S; Poulos, Thomas L (2017) Effect of Redox Partner Binding on Cytochrome P450 Conformational Dynamics. J Am Chem Soc 139:13193-13199 |
| Pensa, Anthony V; Cinelli, Maris A; Li, Huiying et al. (2017) Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors. J Med Chem 60:7146-7165 |
| Meneghini, Luz M; Tripathi, Sarvind; Woodworth, Marcus A et al. (2017) Dissecting binding of a ?-barrel membrane protein by phage display. Mol Biosyst 13:1438-1447 |
| Chreifi, Georges; Dejam, Dillon; Poulos, Thomas L (2017) Crystal structure and functional analysis of Leishmania major pseudoperoxidase. J Biol Inorg Chem 22:919-927 |
| Hollingsworth, Scott A; Nguyen, Brian D; Chreifi, Georges et al. (2017) Insights into the Dynamics and Dissociation Mechanism of a Protein Redox Complex Using Molecular Dynamics. J Chem Inf Model 57:2344-2350 |
| Poulos, Thomas L; Li, Huiying (2017) Nitric oxide synthase and structure-based inhibitor design. Nitric Oxide 63:68-77 |
| Benabbas, Abdelkrim; Sun, Yuhan; Poulos, Thomas L et al. (2017) Ultrafast CO Kinetics in Heme Proteins: Adiabatic Ligand Binding and Heavy Atom Tunneling. J Am Chem Soc 139:15738-15747 |
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