Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2009 Jun 30;10626:10482-6. doi: 10.1073/pnas.0813396106.
Show Gene links
Show Anatomy links
Molecular recognition and self-assembly special feature: Calix[4]arene-based conical-shaped ligands for voltage-dependent potassium channels.
Martos V
,
Bell SC
,
Santos E
,
Isacoff EY
,
Trauner D
,
de Mendoza J
.
???displayArticle.abstract???
Potassium channels are among the core functional elements of life because they underpin essential cellular functions including excitability, homeostasis, and secretion. We present here a series of multivalent calix[4]arene ligands that bind to the surface of voltage-dependent potassium channels (K(v)1.x) in a reversible manner. Molecular modeling correctly predicts the best candidates with a conical C(4) symmetry for optimal binding, and the effects on channel function are assessed electrophysiologically. Reversible inhibition was observed, without noticeable damage of the oocytes, for tetraacylguanidinium or tetraarginine members of the series with small lower rim O-substituents. Apparent binding constants were in the low micromolar range and had Hill coefficients of 1, consistent with a single site of binding. Suppression of current amplitude was accompanied by a positive shift in the voltage dependence of gating and slowing of both voltage sensor motion and channel opening. These effects are in keeping with expectations for docking in the central pore and interaction with the pore domain "turret."
Ader,
A structural link between inactivation and block of a K+ channel.
2008, Pubmed
Ader,
A structural link between inactivation and block of a K+ channel.
2008,
Pubmed
Baldini,
Calixarene-based multivalent ligands.
2007,
Pubmed
Blaustein,
Tethered blockers as molecular 'tape measures' for a voltage-gated K+ channel.
2000,
Pubmed
,
Xenbase
Coghlan,
Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress.
2001,
Pubmed
Glauner,
Spectroscopic mapping of voltage sensor movement in the Shaker potassium channel.
1999,
Pubmed
,
Xenbase
Gordo,
Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand.
2008,
Pubmed
Gradl,
Protein surface recognition by rational design: nanomolar ligands for potassium channels.
2003,
Pubmed
,
Xenbase
Gross,
Agitoxin footprinting the shaker potassium channel pore.
1996,
Pubmed
,
Xenbase
Imredy,
A snake toxin inhibitor of inward rectifier potassium channel ROMK1.
1998,
Pubmed
,
Xenbase
Jiang,
X-ray structure of a voltage-dependent K+ channel.
2003,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Loots,
Protein rearrangements underlying slow inactivation of the Shaker K+ channel.
1998,
Pubmed
MacKinnon,
Potassium channels.
2003,
Pubmed
Magis,
Structure-based secondary structure-independent approach to design protein ligands: Application to the design of Kv1.2 potassium channel blockers.
2006,
Pubmed
Mannuzzu,
Direct physical measure of conformational rearrangement underlying potassium channel gating.
1996,
Pubmed
,
Xenbase
Mannuzzu,
Independence and cooperativity in rearrangements of a potassium channel voltage sensor revealed by single subunit fluorescence.
2000,
Pubmed
,
Xenbase
Pathak,
Closing in on the resting state of the Shaker K(+) channel.
2007,
Pubmed
Perozo,
Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels.
1993,
Pubmed
Schmuck,
Amino acid binding by 2-(guanidiniocarbonyl)pyridines in aqueous solvents: a comparative binding study correlating complex stability with stereoelectronic factors.
2005,
Pubmed
Wang,
An extensive test of 14 scoring functions using the PDBbind refined set of 800 protein-ligand complexes.
2004,
Pubmed
Wulff,
K+ channel modulators for the treatment of neurological disorders and autoimmune diseases.
2008,
Pubmed