ArticleNature2013
The structural mechanism of KCNH-channel regulation by the eag domain.
Article in Nature, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 126 citations in OpenAlex.
- Alternative splicing governs cone cyclic nucleotide-gated (CNG) channel sensitivity to regulation by phosphoinositides.The Journal of biological chemistry · 2014Trial
- Forward genetics reveals a conserved CNBHD-CNBHD interface that restrains EAG channel activation to regulate sleep.PLoS genetics · 2026Article
- The PAS domain directly regulates hERG channel gating in patch-clamp fluorometry recordings.Biophysical journal · 2026Article
- Chlorpromazine inhibits EAG1 channels by altering the interdomain coupling.Biophysical journal · 2026Article
- Developing a Replicable Cardiogenetic Care Model: Insights from the Saguenay-Lac-Saint-Jean Founder Population.Journal of community genetics · 2026Article
- Encapsulins in Terpene Biosynthesis: Enzyme Nanoreactors in Bacterial Secondary Metabolism.Biochemistry · 2026Review
- The molecular basis of KCNH1-related epileptic encephalopathy and the challenge of developing targeted therapeutics.Brain : a journal of neurology · 2026Review
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- Lipid-dependent regulation of Kv10.1 in cancer: implications of membrane remodeling for channel function and pharmacology.Frontiers in pharmacology · 2026Review
- Gating modulation and potentiation of amiodarone blockage of the Kv10.1 potassium channel bu KB130015, an amiodarone derived molecule.Channels (Austin, Tex.) · 2025Article
- GORK KNature communications · 2025Article
- The biosynthesis of the odorant 2-methylisoborneol is compartmentalized inside a protein shell.Nature communications · 2024Article
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- The biosynthesis of the odorant 2-methylisoborneol is compartmentalized inside a protein shell.bioRxiv : the preprint server for biology · 2024Article
- Photo-crosslinking hERG channels causes a U.V.-driven, state-dependent disruption of kinetics and voltage dependence of activation.bioRxiv : the preprint server for biology · 2024Article
- Voltage-gated potassium channels and genetic epilepsy.Frontiers in neurology · 2024Review
- Use of Surface Plasmon Resonance Technique for Studies of Inter-domain Interactions in Ion Channels.Methods in molecular biology (Clifton, N.J.) · 2024Article
- 14-3-3 proteins regulate cullin 7-mediated Eag1 degradation.Cell & bioscience · 2023Article
- Article
- Phenotypic expansion of KCNH1-associated disorders to include isolated epilepsy and its associations with genotypes and molecular sub-regional locations.CNS neuroscience & therapeutics · 2023Article
20 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The KCNH voltage-dependent potassium channels (ether-à-go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4-S5 linker or the CNBHD. Here we present a 2 Å resolution crystal structure of the eag domain-CNBHD complex of the mouse EAG1 (also known as KCNH1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain primarily involves the CNBHD. Notably, the structure reveals that a number of LQT2 mutations at homologous positions in human ERG, in addition to cancer-associated mutations in EAG channels, localize to the eag domain-CNBHD interface. Furthermore, mutations at the interface produced marked effects on channel gating, demonstrating the important physiological role of the eag domain-CNBHD interaction. Our structure of the eag domain-CNBHD complex of mouse EAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.