Allosteric activation and tuning of ligand efficacy in cyclic-nucleotide-gated channels

Gareth R. Tibbs, Evan H. Goulding and Steven A. Siegelbaum
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Gareth R. Tibbs: Howard Hughes Medical Institute, Columbia University
Evan H. Goulding: Howard Hughes Medical Institute, Columbia University
Steven A. Siegelbaum: Howard Hughes Medical Institute, Columbia University

Nature, 1997, vol. 386, issue 6625, 612-615

Abstract: Abstract Despite recent advances in the identification of ligand-binding1,2 and voltage-sensing3 regions of ion channels, the domains that couple such regions to channel opening have not been identified. Moreover, it is uncertain whether ligand binding or depolarization are obligatory steps that must precede channel opening (according to linear reaction schemes4,5) or whether they act to stabilize the channel in an open state that can exist independently of ligand binding or depolarization (according to cyclic allosteric models6–8). By comparing ligand-independent and ligand-dependent channel openings, we now show that retinal and olfactory cyclic-nucleotide-gated channels2 are activated by a cyclic allosteric mechanism. We further show that an amino-terminal domain, distinct from the pore and ligand-binding motifs, participates in the allosteric gating transition, accounting for differences in the free energy of gating of the two channels. The allosteric transition provides an important mechanism for tuning the physiological response of ligand-binding proteins, such as cyclic-nucleotide-gated channels, to different biological signals.

Date: 1997
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DOI: 10.1038/386612a0

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