(taken from application): The long term goal of this research is to enhance our understanding of the interactions between inhaled anesthetics ante biological macromolecules that are responsible for the state of anesthesia. A general hypothesis underlying the work in this program is that occupancy of internal cavities stabilizes protein structure and dynamics, reducing the conformational freedom necessary for normal function. Initial work relied heavily on synthetic peptides, from which insight into the minimal structural requirements for anesthetic binding was gained. In this cycle, more biologically relevant models will be studied. Thus, in one project, not only will binding to synthetic targets be continued, but protein candidates from the Protein Data Bank, selected based on the presence, distribution and character of internal cavities, will be examined for binding and stabilization by volatile anesthetics. Further, because of the need to locate and characterize anesthetic binding in membrane protein, considerable effort will be devoted to developing novel photolabel mimics of the inhaled anesthetics. One project will continue the effort to optimize anesthetic binding sites using synthetic bundle scaffolds, but now include new designs for insertion into lipid bilayers. Because of the probability that membrane proteins are important anesthetic targets, one project will further explore the effect of anesthetics on the structure and function of mammalian rhodopsin and its associated signal transduction mechanism. This project continue work aim at defining the thermodynamics of anesthetic/protein interactions with a series of well-characterized folding models to evaluate the relationship between stabilization and unfolded surface area. Another project will continue its aim of characterizing the structural and dynamic features of anesthetic macromolecular interactions using molecular dynamics simulations. Initial work with lipid bilayers and simple soluble helical bundles will logically lead to bundled peptides in lipid. Finally, the structural features of lipid, and protein bundles will be studied with neutron interferometry in one new project. These structural studies will probe the consequences of anesthetic binding, as well as verify the location, orientation and distribution within the macromolecular matrix. Cores, and for protein synthesis support the five projects.
| 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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