Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

44-POS Board 44 Virtual Rescuing of CNG F547L Mutant Channel by Cyclic Nucleotide Analogues Iliana I. Lozano-M., Estela Ruiz-Baca, Leticia Saucedo-Mendiola, Angelica Lopez-Rodriguez . Fac. C. Quimicas UJED, Durango, Durango, Mexico. Cyclic nucleotide-gated (CNG) channels are critical to the photo transduction cascade that underlie in vertebrate vision. These channels open and close in response to light-induced changes in the intracellular cyclic GMP concentration. Approximately, 75% of the mutations related to achromatopsia, a retinal disorder with impaired color vision, are in the genes encoding CNG channels. The F547L mutation is located at the cyclic nucleotide binding domain (CNBD) in the CNG A3 subunit. This mutant channel reaches the plasma membrane, but it is not functional at 37 o C. Interestingly, its function is rescued at 27 o C or by co-expressing CNG ß subunits; nevertheless, apparent affinity to cGMP is increased, suggesting that correct folding of the protein can be induced leading to the functional rescue of the channel. We have modelled the human CNGA3 channel and the CNGA3 F547L mutant using as template the crystal structure of the C. elegans CNG channel. The model of the mutant suggests a constriction of the structure due to formation of new hydrogen bonds. By docking, we also tested the affinity of natural CNG channel ligands such as cGMP and cAMP along with twelve cyclic nucleotide analogues. Supporting the increased apparent affinity for ligand, previously reported, CNGA3 F547L mutation induces the reduction in size and volume of CNBD, increasing the score affinity for most of the ligands tested, except two molecules that we consider good candidates to rescue the mutant channel function as they keep the same score affinity in the wild type and mutant channel.

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