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PDBsum entry 4kl1
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Protein transport
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PDB id
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4kl1
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PDB id:
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| Name: |
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Protein transport
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Title:
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Hcn4 cnbd in complex with cgmp
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Structure:
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Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4. Chain: a, b, c, d. Fragment: c-terminal domain (unp residues 521-723). Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: hcn4. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.70Å
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R-factor:
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0.214
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R-free:
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0.272
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Authors:
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M.Lolicato,C.Arrigoni,S.Zucca,M.Nardini,A.Bucchi,I.Schroeder, K.Simmons,M.Bolognesi,D.Difrancesco,F.Schwede,C.W.G.Fishwick, A.P.K.Johnson,G.Thiel,A.Moroni
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Key ref:
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M.Lolicato
et al.
(2014).
Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.
Nat Chem Biol,
10,
457-462.
PubMed id:
DOI:
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Date:
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07-May-13
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Release date:
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30-Apr-14
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PROCHECK
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Headers
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References
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Q9Y3Q4
(HCN4_HUMAN) -
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 from Homo sapiens
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Seq:
Struc:
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1203 a.a.
193 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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Nat Chem Biol
10:457-462
(2014)
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PubMed id:
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Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.
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M.Lolicato,
A.Bucchi,
C.Arrigoni,
S.Zucca,
M.Nardini,
I.Schroeder,
K.Simmons,
M.Aquila,
D.DiFrancesco,
M.Bolognesi,
F.Schwede,
D.Kashin,
C.W.Fishwick,
A.P.Johnson,
G.Thiel,
A.Moroni.
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ABSTRACT
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cAMP mediates autonomic regulation of heart rate by means of
hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which
underlie the pacemaker current If. cAMP binding to the C-terminal cyclic
nucleotide binding domain enhances HCN open probability through a conformational
change that reaches the pore via the C-linker. Using structural and functional
analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic
dinucleotides, an emerging class of second messengers in mammals, bind the
C-linker pocket (CLP) and antagonize cAMP regulation of the channel.
Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial
node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence
constitutes an efficient mechanism to hinder β-adrenergic stimulation on If.
Our results highlight the regulative role of the C-linker and identify a
potential drug target in HCN4. Furthermore, these data extend the signaling
scope of cyclic dinucleotides in mammals beyond their first reported role in
innate immune system.
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Links
