Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 2, Pages 592-597Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1013643108
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Funding
- US Department of Energy, Office of Energy Research
- The Howard Hughes Medical Institute
- National Institute of Health [GM079179]
- The David and Lucile Packard Foundation
- National Institutes of Health [5 F31 GM07703]
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Cyclic nucleotide-gated (CNG) channels play an essential role in the visual and olfactory sensory systems and are ubiquitous in eukaryotes. Details of their underlying ion selectivity properties are still not fully understood and are a matter of debate in the absence of high-resolution structures. To reveal the structural mechanism of ion selectivity in CNG channels, particularly their Ca2+ blockage property, we engineered a set of mimics of CNG channel pores for both structural and functional analysis. The mimics faithfully represent the CNG channels they are modeled after, permeate Na+ and K+ equally well, and exhibit the same Ca2+ blockage and permeation properties. Their high-resolution structures reveal a hitherto unseen selectivity filter architecture comprising three contiguous ion binding sites in which Na+ and K+ bind with different ion-ligand geometries. Our structural analysis reveals that the conserved acidic residue in the filter is essential for Ca2+ binding but not through direct ion chelation as in the currently accepted view. Furthermore, structural insight from our CNG mimics allows us to pinpoint equivalent interactions in CNG channels through structure-based mutagenesis that have previously not been predicted using NaK or K+ channel models.
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