Drugs Contort their Targets

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Drugs Contort their Targets
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 d Nuclear Magnetic Resonance Program,
National High Magnetic Field Laboratory,
Tallahassee, Florida 32310-4005, USA
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
924335-4342