This project has as its main goal a full understanding of the binding event, and of binding sites in proteins for at least three currently used anesthetic chemotypes, haloalkanes, haloethers and alkylphenols. This includes an understanding of the features underlying binding energetics (affinity) and selectivity, as well as a characterization of the distribution of such sites in specific proteins, like ion channels. We will accomplish these ambitious goals through two specific aims.
Aim 1 is to design, synthesize and characterize novel chemical tools to discover anesthetic binding sites in complex heteroligomeric ion channel proteins.
Aim 2 will deploy these tools, such as the very successful general anesthetic photolabels, in both ligand and voltage gated ion channels. This latter work both provides and directly tests hypotheses in the other projects. The long range goal is to understand features ofthe ligand and ofthe binding site that underlie selectivity so that the compounds can be altered to enhance on-pathway effects and/or to reduce off-pathway effects. Overall, project 1 is a translational conduit of program derived information to clinical relevance.

Public Health Relevance

General anesthetics are delivered to patients roughly 120 million times per year, world wide. They are the most toxic of all drugs physicians use, and have many troublesome side effects, some durable. This project seeks an understanding of their action through the binding event, and using this information will identify novel chemotypes as the basis for the next generation of general anesthetics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZGM1-PPBC-5)
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University of Pennsylvania
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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
Woll, Kellie A; Skinner, Kenneth A; Gianti, Eleonora et al. (2017) Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling. Biophys J 113:2168-2172
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

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