PDBsum entry 2q0a

Transport protein

PDB id: 2q0a

Contents

Protein chains

194 a.a. *

Ligands

PCG ×2

Waters ×215

* Residue conservation analysis

PDB id:

2q0a

Name:

Transport protein

Title:

Structure and rearrangements in the carboxy-terminal region of spih channels

Structure:

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2. Chain: a, b. Fragment: c-terminal domain (residues 443-640). Synonym: brain cyclic nucleotide-gated channel 2, bcng-2, hyperpolarization-activated cation channel 1, hac-1. Engineered: yes. Mutation: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: hcn2, bcng2, hac1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.25Å R-factor: 0.209 R-free: 0.261

Authors:

G.E.Flynn,K.D.Black,L.D.Islas,B.Sankaran,W.N.Zagotta

Key ref:

G.E.Flynn et al. (2007). Structure and rearrangements in the carboxy-terminal region of SpIH channels. Structure, 15, 671-682. PubMed id: 17562314 DOI: 10.1016/j.str.2007.04.008

Date:

21-May-07 Release date: 19-Jun-07

Protein chains

O88703  (HCN2_MOUSE) -  Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 from Mus musculus

Seq: 863 a.a.

Struc: 194 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/j.str.2007.04.008

Structure 15:671-682 (2007)

PubMed id: 17562314

Structure and rearrangements in the carboxy-terminal region of SpIH channels.

G.E.Flynn, K.D.Black, L.D.Islas, B.Sankaran, W.N.Zagotta.

ABSTRACT

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels regulate the spontaneous firing activity and electrical excitability of many cardiac and neuronal cells. The modulation of HCN channel opening by the direct binding of cAMP underlies many physiological processes such as the autonomic regulation of the heart rate. Here we use a combination of X-ray crystallography and electrophysiology to study the allosteric mechanism for cAMP modulation of HCN channels. SpIH is an invertebrate HCN channel that is activated fully by cAMP, but only partially by cGMP. We exploited the partial agonist action of cGMP on SpIH to reveal the molecular mechanism for cGMP specificity of many cyclic nucleotide-regulated enzymes. Our results also elaborate a mechanism for the allosteric conformational change in the cyclic nucleotide-binding domain and a mechanism for partial agonist action. These mechanisms will likely extend to other cyclic nucleotide-regulated channels and enzymes as well.

Selected figure(s)

Figure 8.
Figure 8. Interactions of cGMP with T592 of the β Roll and I636D of the C Helix
Stereo view showing cGMP in the syn configuration bound to HCN2-I636D. A simulated annealing F[o] − F[c] omit map (green) is shown for cGMP and a 2F[o] − F[c] omit map (blue) is shown for T592 and I636D. Dashed lines indicate hydrogen-bonding interactions between the N2 amine of the guanine ring and T592 and between the N1 and N2 amines of the guanine ring and the carboxylate group of I636D.

Figure 9.
Figure 9. Molecular Mechanism for Conformational Changes Occurring in the CNBD
Model of the cGMP binding and conformational rearrangement that lead to activation of the SpIH channel. The ligand binds to the closed channel primarily through interactions between the β roll and the ribose and phosphate of the cyclic nucleotide. For cGMP, threonine in the β roll plays an important roll in stabilizing cGMP in the syn configuration. The opening allosteric conformational change involves the movement of the C helix relative to the β roll. For cGMP, aspartate in the β roll stabilizes the rearrangement, promoting channel opening.

The above figures are reprinted from an Open Access publication published by Cell Press: Structure (2007, 15, 671-682) copyright 2007.

Figures were selected by an automated process.