The long-term goal of this research is to understand the structural and energetic consequences to a protein target on binding volatile anesthetic molecules. It offers experimental techniques that compliment those peptides in search of a unitary view of what protein structural characteristics select of anesthetic binding and how the energetics of protein-anesthetic interactions alter thermodynamic stability of the secondary, tertiary, and quaternary structure. The investigators propose to determine binding energetics and effects of volatile anesthetic agents on the folding stability of model homopolymers, four-alpha-helix bundles and model ion channels. Several biologic proteins known to bind inhalational anesthetics, such as bovine serum albumen, adenylate kinease, haloalkane dehalogenase, and the luciferases will also be studied. A principle method of analysis will be differential scanning calorimetry and isothermal titration calorimetry. The investigators also propose to determine the effects of volatile anesthetic agents on folding stability and activity of G proteins. Stability analyses will include non-thermal perturbants such as pH and chaotropic agents (urea, guanidium chloride) together with optical approaches including UV absorbance, tryptophan fluorescence, optical rotation, and infrared methods. Finally, the investigators wish to relate the changes in individual signaling protein stability produced by volatile anesthetics as found by the above physical methods to bimolecular signalling using several spectroscopic and other methods developed in this lab. The visual G protein couple signal transduction system will be used because it is a well define representative of the enormous family of G protein couple receptors.
| 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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