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Drugs Contort their Targets

 =21°  =0°.  =32°  =0°.  =38°  =-10°. Jun Hu a,d , Thomas Asbury b, c , Srisairam Achuthan b,c , Conggang Li a,d , Richard Bertram b,c , Jack R. Quine b,c,d , Riqiang Fu d , and Timothy A. Cross a ,b,d.

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Drugs Contort their Targets

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  1. =21° =0° =32° =0° =38° =-10° Jun Hua,d, Thomas Asburyb,c, Srisairam Achuthanb,c, Conggang Lia,d, Richard Bertramb,c, Jack R. Quineb,c,d, Riqiang Fud, and Timothy A. Crossa,b,d a Dept. of Chemistry and Biochemistry, Florida State Univ., Tallahassee, FL 32306, USA b Institute of Molecular Biophysics, Florida State Univ., Tallahassee, FL 32306, USA c Dept. of Mathematics, Florida State Univ., Tallahassee, FL 32306, USA dNuclear Magnetic Resonance Program,National High Magnetic Field Laboratory, Tallahassee, Florida 32310-4005, USA Drugs Contort their Targets Drugs interfere with the function of proteins that conduct specific chemical, physical, and mechanical tasks in living cells. Understanding how these small molecules disrupt these activities is a task for biophysicists. At the NHMFL we are using solid state NMR spectroscopy to determine just how the drug, amantadine disrupts a channel that conducts acid through the influenza viral coat. Surprisingly, the virus thrives on acid and without this channel activity it dies. Amantadine is bound on the channel axis and causes the bundle of four helices to kink and wrap tightly around the drug. The interpretation of the NMR data is shown at the right. Helices cause an cyclical pattern for the magnitude of the signals that has a repeat of 3.6 resonances or amino acids per helical turn. The amplitude of the sine wave tells us the angle that the helical axis makes with respect to the channel axis. In the presence of amanta-dine the tilt angle is smaller and the helix is kinked allowing the bundle wrap tightly around the drug blocking the channel. Supported by AHA (0415075B), NIH (GM-67476 & AI-23007), NHMFL, & Florida State U. J. Hu, T. Asbury, S. Achuthan, C. Li, R. Bertram, J.R. Quine, R. Fu and T.A. Cross (2007) Backbone Structure of the Amantadine-Blocked Trans-Membrane Domain of the M2 Proton Channel from Influenza A Virus. Biophysical Journal 92:4335-4342

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