4HBN

Crystal structure of the human HCN4 channel C-terminus carrying the S672R mutation

Summary for 4HBN

• Entry DOI: 10.2210/pdb4hbn/pdb
• Descriptor: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: camp binding, camp, neuropeptide
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Multi-pass membrane protein: Q9Y3Q4
• Total number of polymer chains: 1
• Total formula weight: 24635.92

Authors

Xu, X.,Marni, F.,Wu, X.,Su, Z.,Musayev, F.,Shrestha, S.,Xie, C.,Gao, W.,Liu, Q.,Zhou, L. (deposition date: 2012-09-28, release date: 2013-01-16, Last modification date: 2024-02-28)

Primary citation

Xu, X.,Marni, F.,Wu, S.,Su, Z.,Musayev, F.,Shrestha, S.,Xie, C.,Gao, W.,Liu, Q.,Zhou, L.
Local and Global Interpretations of a Disease-Causing Mutation near the Ligand Entry Path in Hyperpolarization-Activated cAMP-Gated Channel.
Structure, 20:2116-2123, 2012

PubMed Abstract: 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.

PubMed: 23103389
DOI: 10.1016/j.str.2012.09.017

Experimental method

X-RAY DIFFRACTION (2.6 Å)