+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-13604 | |||||||||
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Title | Apo human Kv3.1 cryo-EM structure | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Potassium ion channel / voltage gated / drug target / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information response to nerve growth factor / globus pallidus development / response to potassium ion / response to fibroblast growth factor / response to auditory stimulus / corpus callosum development / positive regulation of potassium ion transmembrane transport / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / response to light intensity / Voltage gated Potassium channels ...response to nerve growth factor / globus pallidus development / response to potassium ion / response to fibroblast growth factor / response to auditory stimulus / corpus callosum development / positive regulation of potassium ion transmembrane transport / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / response to light intensity / Voltage gated Potassium channels / delayed rectifier potassium channel activity / optic nerve development / neuronal cell body membrane / response to amine / voltage-gated potassium channel activity / action potential / kinesin binding / calyx of Held / axolemma / axon terminus / voltage-gated potassium channel complex / potassium ion transmembrane transport / dendrite membrane / potassium ion transport / cerebellum development / protein tetramerization / protein homooligomerization / response to toxic substance / cellular response to xenobiotic stimulus / presynaptic membrane / postsynaptic membrane / transmembrane transporter binding / cell surface / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.65 Å | |||||||||
Authors | Botte M / Huber S / Bucher D / Klint JK / Rodriguez D / Tagmose L / Chami M / Cheng R / Hennig M / Abdul Rhaman W | |||||||||
Funding support | 1 items
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Citation | Journal: PNAS Nexus / Year: 2022 Title: Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 channel reveal a novel binding site for positive modulators. Authors: Mathieu Botte / Sophie Huber / Denis Bucher / Julie K Klint / David Rodríguez / Lena Tagmose / Mohamed Chami / Robert Cheng / Michael Hennig / Wassim Abdul Rahman / Abstract: Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with ...Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 Å resolution using full-length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well-resolved Zinc site and displaying a rotation by 35°. This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage-gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_13604.map.gz | 1.4 MB | EMDB map data format | |
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Header (meta data) | emd-13604-v30.xml emd-13604.xml | 10.5 KB 10.5 KB | Display Display | EMDB header |
Images | emd_13604.png | 116.3 KB | ||
Filedesc metadata | emd-13604.cif.gz | 5.3 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-13604 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13604 | HTTPS FTP |
-Validation report
Summary document | emd_13604_validation.pdf.gz | 350.6 KB | Display | EMDB validaton report |
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Full document | emd_13604_full_validation.pdf.gz | 350.1 KB | Display | |
Data in XML | emd_13604_validation.xml.gz | 6.8 KB | Display | |
Data in CIF | emd_13604_validation.cif.gz | 7.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13604 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13604 | HTTPS FTP |
-Related structure data
Related structure data | 7pqtMC 7pquC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_13604.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.82 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
-Entire : Detergent solubilized tetramer of human Kv3.1 potassium ion channel
Entire | Name: Detergent solubilized tetramer of human Kv3.1 potassium ion channel |
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Components |
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-Supramolecule #1: Detergent solubilized tetramer of human Kv3.1 potassium ion channel
Supramolecule | Name: Detergent solubilized tetramer of human Kv3.1 potassium ion channel type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Potassium voltage-gated channel subfamily C member 1
Macromolecule | Name: Potassium voltage-gated channel subfamily C member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 58.88318 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MGQGDESERI VINVGGTRHQ TYRSTLRTLP GTRLAWLAEP DAHSHFDYDP RADEFFFDRH PGVFAHILNY YRTGKLHCPA DVCGPLYEE ELAFWGIDET DVEPCCWMTY RQHRDAEEAL DSFGGAPLDN SADDADADGP GDSGDGEDEL EMTKRLALSD S PDGRPGGF ...String: MGQGDESERI VINVGGTRHQ TYRSTLRTLP GTRLAWLAEP DAHSHFDYDP RADEFFFDRH PGVFAHILNY YRTGKLHCPA DVCGPLYEE ELAFWGIDET DVEPCCWMTY RQHRDAEEAL DSFGGAPLDN SADDADADGP GDSGDGEDEL EMTKRLALSD S PDGRPGGF WRRWQPRIWA LFEDPYSSRY ARYVAFASLF FILVSITTFC LETHERFNPI VNKTEIENVR NGTQVRYYRE AE TEAFLTY IEGVCVVWFT FEFLMRVIFC PNKVEFIKNS LNIIDFVAIL PFYLEVGLSG LSSKAAKDVL GFLRVVRFVR ILR IFKLTR HFVGLRVLGH TLRASTNEFL LLIIFLALGV LIFATMIYYA ERIGAQPNDP SASEHTHFKN IPIGFWWAVV TMTT LGYGD MYPQTWSGML VGALCALAGV LTIAMPVPVI VNNFGMYYSL AMAKQKLPKK KKKHIPRPPQ LGSPNYCKSV VNSPH HSTQ SDTCPLAQEE ILEINRAGRK PLRGMSIGSL EVLFQ UniProtKB: Voltage-gated potassium channel KCNC1 |
-Macromolecule #2: POTASSIUM ION
Macromolecule | Name: POTASSIUM ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: K |
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Molecular weight | Theoretical: 39.098 Da |
-Macromolecule #3: water
Macromolecule | Name: water / type: ligand / ID: 3 / Number of copies: 8 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 70.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 362349 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: ANGULAR RECONSTITUTION |