4KL1
HCN4 CNBD in complex with cGMP
Summary for 4KL1
| Entry DOI | 10.2210/pdb4kl1/pdb |
| Related | 1Q3E 3OTF 3U0Z 3U10 3U11 4HBN |
| Descriptor | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, CYCLIC GUANOSINE MONOPHOSPHATE, ACETATE ION, ... (5 entities in total) |
| Functional Keywords | cnbd, camp, cgmp, c-di-gmp, c-di-amp, ion channel, hcn, potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel, camp binding, cgmp binding, protein transport |
| Biological source | Homo sapiens (human) |
| Cellular location | Cell membrane; Multi-pass membrane protein: Q9Y3Q4 |
| Total number of polymer chains | 4 |
| Total formula weight | 96744.53 |
| Authors | Lolicato, M.,Arrigoni, C.,Zucca, S.,Nardini, M.,Bucchi, A.,Schroeder, I.,Simmons, K.,Bolognesi, M.,DiFrancesco, D.,Schwede, F.,Fishwick, C.W.G.,Johnson, A.P.K.,Thiel, G.,Moroni, A. (deposition date: 2013-05-07, release date: 2014-04-30, Last modification date: 2024-11-06) |
| Primary citation | Lolicato, M.,Bucchi, A.,Arrigoni, C.,Zucca, S.,Nardini, M.,Schroeder, I.,Simmons, K.,Aquila, M.,DiFrancesco, D.,Bolognesi, M.,Schwede, F.,Kashin, D.,Fishwick, C.W.,Johnson, A.P.,Thiel, G.,Moroni, A. Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness. Nat.Chem.Biol., 10:457-462, 2014 Cited by PubMed Abstract: 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. PubMed: 24776929DOI: 10.1038/nchembio.1521 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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