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PDBsum entry 2q0a
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Transport protein
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PDB id
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2q0a
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References listed in PDB file
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Key reference
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Title
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Structure and rearrangements in the carboxy-Terminal region of spih channels.
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Authors
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G.E.Flynn,
K.D.Black,
L.D.Islas,
B.Sankaran,
W.N.Zagotta.
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Ref.
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Structure, 2007,
15,
671-682.
[DOI no: ]
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PubMed id
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Abstract
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Hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels
regulate the spontaneous firing activity and electrical excitability of many
cardiac and neuronal cells. The modulation of HCN channel opening by the direct
binding of cAMP underlies many physiological processes such as the autonomic
regulation of the heart rate. Here we use a combination of X-ray crystallography
and electrophysiology to study the allosteric mechanism for cAMP modulation of
HCN channels. SpIH is an invertebrate HCN channel that is activated fully by
cAMP, but only partially by cGMP. We exploited the partial agonist action of
cGMP on SpIH to reveal the molecular mechanism for cGMP specificity of many
cyclic nucleotide-regulated enzymes. Our results also elaborate a mechanism for
the allosteric conformational change in the cyclic nucleotide-binding domain and
a mechanism for partial agonist action. These mechanisms will likely extend to
other cyclic nucleotide-regulated channels and enzymes as well.
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Figure 8.
Figure 8. Interactions of cGMP with T592 of the β Roll and
I636D of the C Helix
Stereo view showing cGMP in the syn
configuration bound to HCN2-I636D. A simulated annealing F[o]
− F[c] omit map (green) is shown for cGMP and a 2F[o] − F[c]
omit map (blue) is shown for T592 and I636D. Dashed lines
indicate hydrogen-bonding interactions between the N2 amine of
the guanine ring and T592 and between the N1 and N2 amines of
the guanine ring and the carboxylate group of I636D.
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Figure 9.
Figure 9. Molecular Mechanism for Conformational Changes
Occurring in the CNBD
Model of the cGMP binding and
conformational rearrangement that lead to activation of the SpIH
channel. The ligand binds to the closed channel primarily
through interactions between the β roll and the ribose and
phosphate of the cyclic nucleotide. For cGMP, threonine in the
β roll plays an important roll in stabilizing cGMP in the syn
configuration. The opening allosteric conformational change
involves the movement of the C helix relative to the β roll.
For cGMP, aspartate in the β roll stabilizes the rearrangement,
promoting channel opening.
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The above figures are
reprinted
from an Open Access publication published by Cell Press:
Structure
(2007,
15,
671-682)
copyright 2007.
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