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- PDB-6uiw: Cryo-EM structure of human CALHM2 in a ruthenium red-bound inhibi... -
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Basic information
Entry | Database: PDB / ID: 6uiw | ||||||
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Title | Cryo-EM structure of human CALHM2 in a ruthenium red-bound inhibited state | ||||||
![]() | Calcium homeostasis modulator protein 2 | ||||||
![]() | TRANSPORT PROTEIN/INHIBITOR / calcium homeostasis modulator / CALHM2 / ![]() | ||||||
Function / homology | Calcium homeostasis modulator family / Calcium homeostasis modulator protein 2 / Calcium homeostasis modulator / ![]() ![]() | ||||||
Biological species | ![]() ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Lu, W. / Du, J. / Choi, W. | ||||||
![]() | ![]() Title: The structures and gating mechanism of human calcium homeostasis modulator 2. Authors: Wooyoung Choi / Nicolina Clemente / Weinan Sun / Juan Du / Wei Lü / ![]() Abstract: Calcium homeostasis modulators (CALHMs) are voltage-gated, Ca-inhibited nonselective ion channels that act as major ATP release channels, and have important roles in gustatory signalling and neuronal ...Calcium homeostasis modulators (CALHMs) are voltage-gated, Ca-inhibited nonselective ion channels that act as major ATP release channels, and have important roles in gustatory signalling and neuronal toxicity. Dysfunction of CALHMs has previously been linked to neurological disorders. Here we present cryo-electron microscopy structures of the human CALHM2 channel in the Ca-free active or open state and in the ruthenium red (RUR)-bound inhibited state, at resolutions up to 2.7 Å. Our work shows that purified CALHM2 channels form both gap junctions and undecameric hemichannels. The protomer shows a mirrored arrangement of the transmembrane domains (helices S1-S4) relative to other channels with a similar topology, such as connexins, innexins and volume-regulated anion channels. Upon binding to RUR, we observed a contracted pore with notable conformational changes of the pore-lining helix S1, which swings nearly 60° towards the pore axis from a vertical to a lifted position. We propose a two-section gating mechanism in which the S1 helix coarsely adjusts, and the N-terminal helix fine-tunes, the pore size. We identified a RUR-binding site near helix S1 that may stabilize this helix in the lifted conformation, giving rise to channel inhibition. Our work elaborates on the principles of CALHM2 channel architecture and symmetry, and the mechanism that underlies channel inhibition. | ||||||
Validation Report | ![]() ![]() ![]() | ||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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-Related structure data
Related structure data | ![]() 20789CM ![]() 6uivC ![]() 6uixC C: citing same article ( M: map data used to model this data |
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Similar-shape strucutres |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 37198.676 Da / Num. of mol.: 11 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() #2: Chemical | ChemComp-R2R / ![]() Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: ![]() |
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Sample preparation
Component | Name: human CALHM2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() |
Specimen support | Details: unspecified |
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![]() ![]() |
Specimen holder | Cryogen: NITROGEN |
Image recording | Average exposure time: 8 sec. / Electron dose: 54.4 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
EM software |
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CTF correction![]() | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 716120 | ||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry![]() ![]() | ||||||||||||||||||||||||||||||||||||
3D reconstruction![]() | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 83728 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: AB INITIO MODEL / Space: REAL |