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- PDB-9ed1: Cryo-EM structure of the human KCa3.1/calmodulin channel in compl... -

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Basic information

Entry
Database: PDB / ID: 9ed1
TitleCryo-EM structure of the human KCa3.1/calmodulin channel in complex with Ca2+ and 1,4-dihydropyridine (DHP-103)
Components
  • Calmodulin-1
  • Intermediate conductance calcium-activated potassium channel protein 4
KeywordsTRANSPORT PROTEIN / Ion channel / Membrane protein / Ca-binding protein
Function / homology
Function and homology information


intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / stabilization of membrane potential / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / establishment of protein localization to mitochondrial membrane ...intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / stabilization of membrane potential / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / establishment of protein localization to membrane / cell volume homeostasis / phospholipid translocation / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / nitric-oxide synthase binding / positive regulation of T cell receptor signaling pathway / regulation of synaptic vesicle exocytosis / calcineurin-mediated signaling / adenylate cyclase binding / regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / immune system process / detection of calcium ion / catalytic complex / regulation of synaptic vesicle endocytosis / regulation of cardiac muscle contraction / potassium channel activity / postsynaptic cytosol / cellular response to interferon-beta / phosphatidylinositol 3-kinase binding / calcium channel inhibitor activity / presynaptic cytosol / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / sperm midpiece / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / regulation of heart rate / calyx of Held / response to amphetamine / adenylate cyclase activator activity / sarcomere / nitric-oxide synthase regulator activity / protein serine/threonine kinase activator activity / regulation of cytokinesis / positive regulation of protein secretion / spindle microtubule / calcium channel regulator activity / positive regulation of receptor signaling pathway via JAK-STAT / establishment of localization in cell / defense response / response to calcium ion / potassium ion transport / cellular response to type II interferon / G2/M transition of mitotic cell cycle / Schaffer collateral - CA1 synapse / ruffle membrane / spindle pole / calcium-dependent protein binding / calcium ion transport / myelin sheath / growth cone / protein phosphatase binding / protein homotetramerization / vesicle / transmembrane transporter binding / calmodulin binding / neuron projection / protein domain specific binding / neuronal cell body / calcium ion binding / centrosome / protein kinase binding / protein homodimerization activity / protein-containing complex / mitochondrion / nucleoplasm / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / : / EF-hand domain pair ...Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
: / Intermediate conductance calcium-activated potassium channel protein 4 / Calmodulin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsNam, Y.W. / Zhang, M.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)4R33 NS101182-03 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1R15 NS130420-01A1 United States
American Heart Association23AIREA1039423 United States
American Heart Association24CDA1260237 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel K3.1.
Authors: Seow Theng Ong / Young-Woo Nam / Joshua A Nasburg / Alena Ramanishka / Xuan Rui Ng / Zhong Zhuang / Stephanie Shee Min Goay / Hai M Nguyen / Latika Singh / Vikrant Singh / Alicia Rivera / M ...Authors: Seow Theng Ong / Young-Woo Nam / Joshua A Nasburg / Alena Ramanishka / Xuan Rui Ng / Zhong Zhuang / Stephanie Shee Min Goay / Hai M Nguyen / Latika Singh / Vikrant Singh / Alicia Rivera / M Elaine Eyster / Yang Xu / Seth L Alper / Heike Wulff / Miao Zhang / K George Chandy /
Abstract: The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery ...The 1,4-dihydropyridines, drugs with well-established bioavailability and toxicity profiles, have proven efficacy in treating human hypertension, peripheral vascular disorders, and coronary artery disease. Every 1,4-dihydropyridine in clinical use blocks L-type voltage-gated calcium channels. We now report our development, using selective optimization of a side activity (SOSA), of a class of 1,4-dihydropyridines that selectively and potently inhibit the intermediate-conductance calcium-activated K channel K3.1, a validated therapeutic target for diseases affecting many organ systems. One of these 1,4-dihydropyridines, DHP-103, blocked K3.1 with an IC of 6 nM and exhibited exquisite selectivity over calcium channels and a panel of >100 additional molecular targets. Using high-resolution structure determination by cryogenic electron microscopy together with mutagenesis and electrophysiology, we delineated the drug binding pocket for DHP-103 within the water-filled central cavity of the K3.1 channel pore, where bound drug directly impedes ion permeation. DHP-103 inhibited gain-of-function mutant K3.1 channels that cause hereditary xerocytosis, suggesting its potential use as a therapeutic for this hemolytic anemia. In a rat model of acute ischemic stroke, the second leading cause of death worldwide, DHP-103 administered 12 h postischemic insult in proof-of-concept studies reduced infarct volume, improved balance beam performance (measure of proprioception) and decreased numbers of activated microglia in infarcted areas. K3.1-selective 1,4-dihydropyridines hold promise for the many diseases for which K3.1 has been experimentally confirmed as a therapeutic target.
History
DepositionNov 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2025Provider: repository / Type: Initial release
Revision 1.1May 7, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Intermediate conductance calcium-activated potassium channel protein 4
B: Intermediate conductance calcium-activated potassium channel protein 4
C: Intermediate conductance calcium-activated potassium channel protein 4
D: Intermediate conductance calcium-activated potassium channel protein 4
E: Calmodulin-1
F: Calmodulin-1
G: Calmodulin-1
H: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)236,69525
Polymers236,0198
Non-polymers67617
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Intermediate conductance calcium-activated potassium channel protein 4 / SKCa 4 / SKCa4 / hSK4 / Gardos channel / IKCa1 / hIK1 / KCa3.1 / Putative Gardos channel / hKCa4


Mass: 42598.633 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNN4, IK1, IKCA1, KCA4, SK4 / Production host: Homo sapiens (human) / References: UniProt: O15554
#2: Protein
Calmodulin-1


Mass: 16406.004 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Calm1, Calm, Cam, Cam1, CaMI / Production host: Homo sapiens (human) / References: UniProt: P0DP29
#3: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human SK4-CaM channel complex in the presence of calcium.
Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.23166 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293s / Cell: HEK293s / Plasmid: pEGBacMam
Buffer solutionpH: 8
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2300 nm / Nominal defocus min: 1300 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
7UCSF ChimeraX1.8model fitting
13PHENIX1.21.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 109449 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00215712
ELECTRON MICROSCOPYf_angle_d0.44721252
ELECTRON MICROSCOPYf_dihedral_angle_d3.9492164
ELECTRON MICROSCOPYf_chiral_restr0.0352480
ELECTRON MICROSCOPYf_plane_restr0.0032664

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