4HBN: Crystal Structure Of The Human Hcn4 Channel C-terminus Carrying The S672r Mutation

Hyperpolarization-activated, cAMP-gated (HCN) channels sense membrane potential and intracellular cAMP levels. A mutation identified in the cAMP binding domain (CNBD) of the human HCN4 channel, S672R, severely reduces the heart rate, but the molecular mechanism has been unclear. Our biochemical binding assays on isolated CNBD and patch-clamp recordings on the functional channel show that S672R reduces cAMP binding. The crystal structure of the mutant CNBD revealed no global changes except a disordered loop on the cAMP entry path. To address this localized structural perturbation at a whole protein level, we studied the activity-dependent dynamic interaction between cAMP and the functional channel using the patch-clamp fluorometry technique. S672R reduces the binding of cAMP to the channels in the resting state and significantly increases the unbinding rate during channel deactivation. This study on a disease-causing mutation illustrates the important roles played by the structural elements on the ligand entry-exit path in stabilizing the bound ligand in the binding pocket.
PDB ID: 4HBNDownload
MMDB ID: 106758
PDB Deposition Date: 2012/9/28
Updated in MMDB: 2013/01
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4HBN: tetrameric; determined by author and by software (PISA)
Molecular Components in 4HBN
Label Count Molecule
Proteins (4 molecules)
Potassium/sodium Hyperpolarization-activated Cyclic Nucleotide-gated Channel 4(Gene symbol: HCN4)
Molecule annotation
Chemicals (8 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB