(taken from the application). The investigator plans to examine a) the localization of selected anesthetics within, and b) the resulting perturbation of the structures of, both water soluble and lipid soluble alpha helical bundles possessing designed cavities for high specificity anesthetic binding utilizing state-of-the-art synchrotron radiation-based x-ray scattering and cold neutron scattering techniques. Because such de novo designed """"""""maquettes"""""""" based on alpha helical bundle motifs can be vectorially-oriented within single monolayer and single bilayer systems, they are particularly amenable to detailed structural studies employing these techniques without the requirement of single crystals thereof, either two- or three-dimensional. The overall secondary, tertiary and quaternary structures of these bundles, together with selected portions of the secondary structures of these synthetic artificial protein """"""""maquettes"""""""" will be of particular interest. Since such de novo designed """"""""maquettes"""""""" based on alpha helical bundle motifs can mimic a variety of the important biological functions of both soluble and membrane proteins, including enzyme catalysis and specific ion channel activity, it is anticipated that these structural studies will provide considerable insight into possible mechanisms of anesthetic action based on protein targets, especially when combined with detailed molecular dynamics computer simulations of these same systems.
| 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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