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.
Structure
2007 Jun 01;156:655-70. doi: 10.1016/j.str.2007.04.012.
Show Gene links
Show Anatomy links
Gating of HCN channels by cyclic nucleotides: residue contacts that underlie ligand binding, selectivity, and efficacy.
Zhou L
,
Siegelbaum SA
.
???displayArticle.abstract???
Cyclic nucleotides (cNMPs) regulate the activity of various proteins by interacting with a conserved cyclic nucleotide-binding domain (CNBD). Although X-ray crystallographic studies have revealed the structures of several CNBDs, the residues responsible for generating the high efficacy with which ligand binding leads to protein activation remain unknown. Here, we combine molecular dynamics simulations with mutagenesis to identify ligand contacts important for the regulation of the hyperpolarization-activated HCN2 channel by cNMPs. Surprisingly, out of 7 residues that make strong contacts with ligand, only R632 in the C helix of the CNBD is essential for high ligand efficacy, due to its selective stabilization of cNMP binding to the open state of the channel. Principal component analysis suggests that a local movement of the C helix upon ligand binding propagates through the CNBD of one subunit to the C linker of a neighboring subunit to apply force to the gate of the channel.
Altenhofen,
Control of ligand specificity in cyclic nucleotide-gated channels from rod photoreceptors and olfactory epithelium.
1991, Pubmed,
Xenbase
Altenhofen,
Control of ligand specificity in cyclic nucleotide-gated channels from rod photoreceptors and olfactory epithelium.
1991,
Pubmed
,
Xenbase
Amadei,
Essential dynamics of proteins.
1993,
Pubmed
Aqvist,
A new method for predicting binding affinity in computer-aided drug design.
1994,
Pubmed
Berman,
The cAMP binding domain: an ancient signaling module.
2005,
Pubmed
Berrera,
cAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations.
2006,
Pubmed
Brown,
How does adrenaline accelerate the heart?
1979,
Pubmed
Canutescu,
A graph-theory algorithm for rapid protein side-chain prediction.
2003,
Pubmed
Chen,
Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide.
2001,
Pubmed
,
Xenbase
Clayton,
Structural basis of ligand activation in a cyclic nucleotide regulated potassium channel.
2004,
Pubmed
Craven,
CNG and HCN channels: two peas, one pod.
2006,
Pubmed
Dittrich,
PcrA helicase, a prototype ATP-driven molecular motor.
2006,
Pubmed
Fan,
Refinement of homology-based protein structures by molecular dynamics simulation techniques.
2004,
Pubmed
García,
Large-amplitude nonlinear motions in proteins.
1992,
Pubmed
Georgescu,
Combining conformational flexibility and continuum electrostatics for calculating pK(a)s in proteins.
2002,
Pubmed
Gordon,
Altered ligand specificity by protonation in the ligand binding domain of cyclic nucleotide-gated channels.
1996,
Pubmed
,
Xenbase
Goulding,
Molecular cloning and single-channel properties of the cyclic nucleotide-gated channel from catfish olfactory neurons.
1992,
Pubmed
Goulding,
Molecular mechanism of cyclic-nucleotide-gated channel activation.
1994,
Pubmed
,
Xenbase
Gullingsrud,
Dynamic binding of PKA regulatory subunit RI alpha.
2006,
Pubmed
Honig,
Classical electrostatics in biology and chemistry.
1995,
Pubmed
Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed
Ichiye,
Collective motions in proteins: a covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations.
1991,
Pubmed
Johnson,
Rotational movement during cyclic nucleotide-gated channel opening.
2001,
Pubmed
,
Xenbase
Ludwig,
A family of hyperpolarization-activated mammalian cation channels.
1998,
Pubmed
Matulef,
Multimerization of the ligand binding domains of cyclic nucleotide-gated channels.
2002,
Pubmed
,
Xenbase
Mazzolini,
Movement of the C-helix during the gating of cyclic nucleotide-gated channels.
2002,
Pubmed
,
Xenbase
Passner,
The structure of a CAP-DNA complex having two cAMP molecules bound to each monomer.
1997,
Pubmed
Renaudon,
Nucleotide modulation of f-channel activity in rabbit sino-atrial node myocytes.
1998,
Pubmed
Robinson,
Hyperpolarization-activated cation currents: from molecules to physiological function.
2003,
Pubmed
Rocchia,
Rapid grid-based construction of the molecular surface and the use of induced surface charge to calculate reaction field energies: applications to the molecular systems and geometric objects.
2002,
Pubmed
Santoro,
Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain.
1998,
Pubmed
,
Xenbase
Schüttelkopf,
PRODRG: a tool for high-throughput crystallography of protein-ligand complexes.
2004,
Pubmed
Shabb,
Mutating protein kinase cAMP-binding sites into cGMP-binding sites. Mechanism of cGMP selectivity.
1991,
Pubmed
Tibbs,
A state-independent interaction between ligand and a conserved arginine residue in cyclic nucleotide-gated channels reveals a functional polarity of the cyclic nucleotide binding site.
1998,
Pubmed
,
Xenbase
Tibbs,
Allosteric activation and tuning of ligand efficacy in cyclic-nucleotide-gated channels.
1997,
Pubmed
,
Xenbase
Varnum,
Molecular mechanism for ligand discrimination of cyclic nucleotide-gated channels.
1995,
Pubmed
Vigil,
A simple electrostatic switch important in the activation of type I protein kinase A by cyclic AMP.
2006,
Pubmed
Wainger,
Molecular mechanism of cAMP modulation of HCN pacemaker channels.
2001,
Pubmed
Wang,
Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.
2002,
Pubmed
,
Xenbase
Young,
Distinct structural determinants of efficacy and sensitivity in the ligand-binding domain of cyclic nucleotide-gated channels.
2004,
Pubmed
,
Xenbase
Zagotta,
Structural basis for modulation and agonist specificity of HCN pacemaker channels.
2003,
Pubmed
Zhou,
A conserved tripeptide in CNG and HCN channels regulates ligand gating by controlling C-terminal oligomerization.
2004,
Pubmed
,
Xenbase
