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Anesthetic Modulation of Protein Dynamics: Insight from an NMR Study

Anesthetic Modulation of Protein Dynamics: Insight from an NMR Study . Presented by: Logan Woodall Mentor: Dr. Pei Tang. Mistic. A 4 a- helix bundle in the transmembrane domain of Cys-loop family of receptors. Experimental Setup.

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Anesthetic Modulation of Protein Dynamics: Insight from an NMR Study

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  1. Anesthetic Modulation of Protein Dynamics: Insight from an NMR Study Presented by: Logan Woodall Mentor: Dr. Pei Tang

  2. Mistic • A 4 a-helix bundle in the transmembrane domain of Cys-loop family of receptors

  3. Experimental Setup • 1H-15N TROSY-HSQC spectra used to determine dissociation constants • STD tests to confirm direct Mistic-anesthetic interaction • Magnetic pulse sequences used to study protein dynamics

  4. Remarkable chemical shifts after exposure to halothane Certain residues’ signals were also either strengthened (i.e. S58) or weakened (i.e. I52) Sites of Halothane Interaction

  5. TROSY-HSQC Overlay

  6. Sites of Interaction (Contd) • Most helical regions unaffected while loop regions generally interacted with halothane • Binding likely disrupts interaction between different loops or residues within the same loop

  7. Sites of Interaction (Contd) • Regions of significant chemical shift localized to residues near/in loops

  8. Halothane Effects on Structure • Relatively small rmsd values indicate conservation of structure upon halothane addition

  9. Halothane Effects on Motion • R2 relaxation rates affected in loops connecting helices and along a2 helix (T39-N45) • Residues T39, N45, and Y82 underwent chemical exchange on mico/millisec time scale (- halothane) but did not undergo chemical exchange (+ halothane)

  10. Effects on Motion (Contd) • Two pairs of nearby residues w/ similar exchange rates affected similarly by halothane addition • Most relaxation dispersion values decreased by halothane • Some residues' chemical shifts not affected by halothane while dynamics were (I52, Y82)

  11. Key Points of Study • Residues with motion on microsecond/millisecond timescale mostly in loops between helices • Residues near each other spatially (but not necessarily sequentially) display concerted motion

  12. Key Points (Contd) • Halothane seemingly capable of altering Mistic slow dynamics through both direct interaction with residues and allosteric modulation • General anesthetics tend to interact preferentially with amphipathic regions of proteins

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