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. Sequence alignments clearly show that the flavin domain is very similar to cytochrome P450 reductase but that the heme domain bears little resemblance to other heme proteins despite the similarity to P450 in both function and spectral properties. Structure of the heme domain for all 3 mammalian isoforms have been determined. The goal now is to determine the structure of various complexes using known inhibitors as well as new inhibitors designed and synthesized as part of this project. In addition, efforts will be made to determine the holo-NOS structure as well as various constructs geared toward understanding the electron transfer properties of NOS. A variety of biochemical and biophysical studies also are planned to complement the crystallographic work.
| 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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