PDBsum entry 4nvp

Transport protein

PDB id: 4nvp

Contents

Protein chain

201 a.a.

Ligands

7CH

Waters ×37

PDB id:

4nvp

Name:

Transport protein

Title:

Structure of the cyclic nucleotide-binding domain of hcn4 channel complexed with 7-ch-camp

Structure:

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hcn4. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.50Å R-factor: 0.201 R-free: 0.270

Authors:

A.Alfieri,A.Moroni

Key ref:

S.Möller et al. (2014). Cyclic nucleotide mapping of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Acs Chem Biol, 9, 1128-1137. PubMed id: 24605759 DOI: 10.1021/cb400904s

Date:

05-Dec-13 Release date: 19-Mar-14

Protein chain

Q9Y3Q4  (HCN4_HUMAN) -  Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 from Homo sapiens

Seq: 1203 a.a.

Struc: 201 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1021/cb400904s

Acs Chem Biol 9:1128-1137 (2014)

PubMed id: 24605759

Cyclic nucleotide mapping of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.

S.Möller, A.Alfieri, D.Bertinetti, M.Aquila, F.Schwede, M.Lolicato, H.Rehmann, A.Moroni, F.W.Herberg.

ABSTRACT

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a central role in the regulation of cardiac and neuronal firing rate, and these channels can be dually activated by membrane hyperpolarization and by binding of cyclic nucleotides. cAMP has been shown to directly bind HCN channels and modulate their activity. Despite this, while there are selective inhibitors that block the activation potential of the HCN channels, regulation by cAMP analogs has not been well investigated. A comprehensive screen of 47 cyclic nucleotides with modifications in the nucleobase, ribose moiety, and cyclic phosphate was tested on the three isoforms HCN1, HCN2, and HCN4. 7-CH-cAMP was identified to be a high affinity binder for HCN channels and crosschecked for its ability to act on other cAMP receptor proteins. While 7-CH-cAMP is a general activator for cAMP- and cGMP-dependent protein kinases as well as for the guanine nucleotide exchange factors Epac1 and Epac2, it displays the highest affinity to HCN channels. The molecular basis of the high affinity was investigated by determining the crystal structure of 7-CH-cAMP in complex with the cyclic nucleotide binding domain of HCN4. Electrophysiological studies demonstrate a strong activation potential of 7-CH-cAMP for the HCN4 channel in vivo. So, this makes 7-CH-cAMP a promising activator of the HCN channels in vitro whose functionality can be translated in living cells.