Project II will study the binding of general anesthetics to designed cavities in a model protein, a designed 4-alpha-helix bundle, and will interpret the results with the aid of interaction parameters derived from gas-liquid partition studies. The central problem in this project is to obtain structures of the designed protein with and without the bound ligand. This project has two aims.
The first aim i s to obtain interaction parameters describing the physics of interaction between groups in a general anesthetic and groups in organic liquids classes to resemble various classes of amino acid side chains in proteins.
Specific aim 2 proposes to use a scaffold formed from a designed 4-alpha-helix bundle protein containing a cavity designed to contain a general anesthetic (GA) such as halothane, measure the structure and dynamics of the protein with and without the bound anesthetic, and measure the binding constant and stoichiometry of the GA-scaffold interaction.
The aim i s to use the results to test the knowledge gained in the first aim to find out if it is adequate to predict, or at least interpret, the properties of a GA-protein cavity interaction and also to explore how binding of a GA to a protein cavity may affect the structure and dynamics of the protein.
| Loll, Patrick J (2018) Structural Analysis of Anesthetics in Complex with Soluble Proteins. Methods Enzymol 603:3-20 |
| Yang, Elaine; Granata, Daniele; Eckenhoff, Roderic G et al. (2018) Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation. J Gen Physiol 150:1299-1316 |
| Woll, Kellie A; Guzik-Lendrum, Stephanie; Bensel, Brandon M et al. (2018) An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules. J Biol Chem 293:11283-11295 |
| Woll, Kellie A; Zhou, Xiaojuan; Bhanu, Natarajan V et al. (2018) Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. FASEB J 32:4172-4189 |
| Kasimova, Marina A; Yazici, Aysenur Torun; Yudin, Yevgen et al. (2018) A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine. J Gen Physiol 150:1554-1566 |
| Wang, Yali; Yang, Elaine; Wells, Marta M et al. (2018) Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites. J Gen Physiol 150:1317-1331 |
| Bensel, Brandon M; Guzik-Lendrum, Stephanie; Masucci, Erin M et al. (2017) Common general anesthetic propofol impairs kinesin processivity. Proc Natl Acad Sci U S A 114:E4281-E4287 |
| Okuno, Toshiaki; Koutsogiannaki, Sophia; Ohba, Mai et al. (2017) Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production. FASEB J 31:1584-1594 |
| Granata, Daniele; Ponzoni, Luca; Micheletti, Cristian et al. (2017) Patterns of coevolving amino acids unveil structural and dynamical domains. Proc Natl Acad Sci U S A 114:E10612-E10621 |
| Carnevale, Vincenzo; Klein, Michael L (2017) Small molecule modulation of voltage gated sodium channels. Curr Opin Struct Biol 43:156-162 |
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