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Open data
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Basic information
Entry | Database: PDB / ID: 9ayl | ||||||
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Title | Cryo-EM structure of human Cav3.2 with ACT-709478 | ||||||
![]() | Voltage-dependent T-type calcium channel subunit alpha-1H | ||||||
![]() | TRANSPORT PROTEIN / Cav3.2 / voltage gated calcium channel / cryo-EM / ACT-709478 | ||||||
Function / homology | ![]() aldosterone biosynthetic process / cortisol biosynthetic process / low voltage-gated calcium channel activity / positive regulation of acrosome reaction / positive regulation of calcium ion-dependent exocytosis / cellular response to potassium ion / high voltage-gated calcium channel activity / voltage-gated monoatomic ion channel activity / myoblast fusion / NCAM1 interactions ...aldosterone biosynthetic process / cortisol biosynthetic process / low voltage-gated calcium channel activity / positive regulation of acrosome reaction / positive regulation of calcium ion-dependent exocytosis / cellular response to potassium ion / high voltage-gated calcium channel activity / voltage-gated monoatomic ion channel activity / myoblast fusion / NCAM1 interactions / calcium ion import / voltage-gated sodium channel complex / membrane depolarization during action potential / inorganic cation transmembrane transport / muscle organ development / voltage-gated calcium channel complex / voltage-gated sodium channel activity / regulation of heart contraction / calcium ion import across plasma membrane / Smooth Muscle Contraction / cellular response to hormone stimulus / muscle contraction / regulation of membrane potential / scaffold protein binding / neuron projection / membrane / metal ion binding / plasma membrane Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å | ||||||
![]() | Fan, X. / Huang, J. / Yan, N. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for human Ca3.2 inhibition by selective antagonists. Authors: Jian Huang / Xiao Fan / Xueqin Jin / Chen Lyu / Qinmeng Guo / Tao Liu / Jiaofeng Chen / Amaël Davakan / Philippe Lory / Nieng Yan / ![]() ![]() ![]() Abstract: The Ca3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Ca3.2 alone ...The Ca3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Ca3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 Å to 3.2 Å. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity. | ||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 262.1 KB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1.6 MB | Display | ![]() |
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Full document | ![]() | 1.6 MB | Display | |
Data in XML | ![]() | 45.2 KB | Display | |
Data in CIF | ![]() | 65.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 43995MC ![]() 9aygC ![]() 9ayhC ![]() 9ayjC ![]() 9aykC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
-Protein / Sugars , 2 types, 3 molecules A![](data/chem/img/NAG.gif)
![](data/chem/img/NAG.gif)
#1: Protein | Mass: 234853.609 Da / Num. of mol.: 1 / Fragment: UNP residues 1-491,772-2353 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#3: Sugar |
-Non-polymers , 5 types, 11 molecules ![](data/chem/img/CA.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/Y01.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/Y01.gif)
#2: Chemical | ChemComp-A1AHK / Mass: 425.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18F3N5O / Feature type: SUBJECT OF INVESTIGATION | ||
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#4: Chemical | ChemComp-CA / | ||
#5: Chemical | ChemComp-LPE / | ||
#6: Chemical | ChemComp-Y01 / #7: Chemical | ChemComp-JL3 / [( Mass: 663.906 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C35H70NO8P |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Voltage-dependent T-type calcium channel subunit alpha-1H Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 188950 / Symmetry type: POINT | ||||||||||||||||||||||||
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