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Structural Research of Calcium Ion-Selective Channels

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The regulation of calcium ion concentrations within cells is tightly controlled by a variety of mechanisms, including the activity of calcium ion-selective channels. These channels are responsible for allowing calcium ions to flow across cellular membranes, and their malfunction has been implicated in a number of diseases, including heart disease, Alzheimer's disease, and cancer.

One of the most well-studied types of calcium ion-selective channels is the voltage-gated calcium (Cav) channel, which is found in a variety of cell types throughout the body. Several high-resolution structures of Cav channel have been obtained using X-ray crystallography and cryo-electron microscopy (cryo-EM) techniques. These structures have revealed the location of important functional domains within the channel, as well as the specific interactions between the channel and various ligands, such as calcium ions and drugs that modulate channel activity.

The Cav1 channels Cav1 channels are hetero-multimeric complexes encompassing various subunits including the pore-forming α1 core subunit and auxiliary subunits α2δ, β, and γ. The α1 subunit folds into four homologous repeats I-IV, which are aligned in a canonical voltage-gated ion channel fold. Each repeat encompasses six transmembrane segments, denoted as S1-S6, which are arranged in two functional entities. The peripheral voltage sensing domain of the Cav1 channels comprises the S1-S4 segments in each repeat. The S5 and S6 segments, in combination with the intervening segments, including the selectivity filters and the supporting helices P1 and P2, derived from the four repeats, ultimately come together to form the central ion-conducting pore domain of these channels.

Molecular basis for rCav1.1 modulation by chemical ligands.Figure 1. Molecular basis for rCav1.1 modulation by chemical ligands. (Zhao Y, et al., 2019)

ProteinOrganismMethodResolutionPDB Entry ID
Ca2+ selectivity of a voltage-gated calcium channel (expressed in Trichoplusia ni)Aliarcobacter butzleriX-ray diffraction2.75 Å4MS2
CavAb voltage-gated calcium channel (expressed in Trichoplusia ni)Aliarcobacter butzleriX-ray diffraction2.70 Å5KLB
Voltage-gated calcium channel Cav1.1 complex (expressed in E. coli)Oryctolagus cuniculusCryo-EM single particle analysis4.20 Å3JBR
Voltage-gated calcium channel Cav1.1 complex (expressed in E. coli)Oryctolagus cuniculusCryo-EM single particle analysis3.60 Å5GJV
Cav1.1-Nifedipine Complex (expressed in E. coli)Oryctolagus cuniculusCryo-EM single particle analysis2.90 Å6JP5
CaV1.1 voltage-gated calcium channel in nanodiscs, in presence of amlodipineOryctolagus cuniculusCryo-EM single particle analysis2.90 Å7JPX
L-type voltage-gated calcium channel Cav1.3 (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.00 Å7UHG
N-type voltage-gated calcium channel Cav2.2 (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.10 Å7MIY
N-type voltage gated calcium channel CaV2.2-alpha2/delta1-beta1 complex, apo state (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis2.80 Å7VFS
Cav2.3 R-type voltage-gated calcium channel, wild-type (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.10 Å8EPL
R-type voltage-gated CaV2.3-alpha2/delta1-beta1 channel complex in the ligand-free (apo) state (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.10 Å7XLQ
CaV3.1 voltage-gated calcium channel (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.30 Å6KZO
Calcium release-activated calcium (CRAC) channel ORAI (expressed in Komagataella pastoris)Drosophila melanogasterX-ray diffraction3.35 Å4HKR
CRAC channel Orai in an open conformation; H206A gain-of-function mutation (expressed in Komagataella pastoris)Drosophila melanogasterX-ray diffraction6.71 Å6BBF
Calcium release-activated calcium channel protein 1, P288L mutant (expressed in HEK293 cells)Drosophila melanogasterX-ray diffraction4.50 Å6AKI
CRAC channel Orai in an open conformation; H206A gain-of-function mutation in complex with an antibody (expressed in Komagataella pastoris)Drosophila melanogasterCryo-EM single particle analysis3.30 Å7KR5
Stromal interaction molecule 1 coiled-coil 1 fragment (expressed in E. coli)Homo sapiensSolution NMR/6YEL
YetJ pH-sensitive calcium-leak channel, pH 8 (closed form) (expressed in E. coli)Bacillus subtilisX-ray diffraction1.95 Å4PGR
YetJ pH-sensitive calcium-leak channel (expressed in E. coli)Bacillus subtilisX-ray diffraction2.50 Å6NQ7
RyR1 ryanodine receptor, closed state in complex with FKBP12 (expressed in E. coli)Oryctolagus cuniculusCryo-EM single particle analysis3.80 Å3J8H
RyR1 (EGTA-only dataset, all particles) (expressed in E. coli)Homo sapiensCryo-EM single particle analysis4.40 Å5TB0
Ryanodine Receptor 1 Repeat12 Domain (expressed in E. coli)Oryctolagus cuniculusX-ray diffraction1.55 Å5C30
Ryanodine Receptor 1 in nanodiscs in the presence of calcium and ATPOryctolagus cuniculusCryo-EM single particle analysis8.20 Å6FOO
RyR1 ryanodine receptor in complex with Ca2+ and chlorantraniliprole (CHL) (expressed in E. coli)Oryctolagus cuniculusCryo-EM single particle analysis4.70 Å7CF9
RyR1 ryanodine receptor embedded in a lipid bilayer, primed model (expressed in E. coli)Oryctolagus cuniculusCryo-EM single particle analysis3.36 Å7M6A
RyR1 in the presence of AMP-PCP in nanodiscOryctolagus cuniculusCryo-EM single particle analysis4.30Å7K0T
Ryanodine Receptor type 1 mutant R164C in complex with FKBP12.6 (expressed in HEK293 cells)Oryctolagus cuniculusCryo-EM single particle analysis3.54 Å6WOT
RyR1 disease mutant Y523S in complex with FKBP12.6 embedded in lipidic nanodisc in the closed state (expressed in HEK293 cells)Oryctolagus cuniculusCryo-EM single particle analysis4.00 Å7T64
RyR2 ryanodine receptor, closed stateSus scrofaCryo-EM single particle analysis4.40 Å5GO9
RyR2 ryanodine receptor bound to FKBP12.6 interacting with human calmodulin (CaM), apo CaM state (expressed in E. coli)Sus scrofaCryo-EM single particle analysis3.60 Å6JI8
RyR2 (Ca2+ alone dataset)Sus scrofaCryo-EM single particle analysis6.10 Å6JG3
RyR2 ryanodine receptor SPRY1 domain critical in binding FKBP12 (expressed in E. coli)Mus musculusX-ray diffraction1.21 Å5C33
RyR2 ryanodine receptor, EGTA dataset, class 1&2, closed state (expressed in HEK293 cells)Mus musculusCryo-EM single particle analysis3.30 Å7VML
InsP3R1 Inositol-1,4,5-trisphosphate receptorRattus norvegicusCryo-EM single particle analysis4.70 Å3JAV
InsP3R1 Inositol-1,4,5-trisphosphate receptor in lipid nanodisc, the apo-stateRattus norvegicusCryo-EM single particle analysis3.30 Å7LHE
InsP3R1 Inositol-1,4,5-trisphosphate receptor in the presence of Calcium/IP3/ATPRattus norvegicusCryo-EM single particle analysis3.50 Å8EAR
InsP3R3 Inositol-1,4,5-trisphosphate receptor, apo state (expressed in Sf9 cells)Homo sapiensCryo-EM single particle analysis3.49 Å6DQJ
InsP3R3 Inositol-1,4,5-trisphosphate receptor and presence of self-binding peptide (expressed in Spodoptera frugiperda)Homo sapiensCryo-EM single particle analysis3.77 Å6UQK
IP3 and ATP bound type 3 IP3 receptor in the pre-active A state (expressed in Spodoptera frugiperda)Homo sapiensCryo-EM single particle analysis3.20 Å7T3P
Mitochondrial calcium uniporter (MCU) (expressed in E. coli)Caenorhabditis elegansSolution NMR/5ID3
Mitochondrial calcium uniporter (MCU), full length (expressed in E. coli)Neurospora crassaCryo-EM single particle analysis3.70 Å6DT0
Mitochondrial calcium uniporter (MCU), full length (expressed in E. coli)Aspergillus fischeriCryo-EM single particle analysis3.80 Å6D7W
Mitochondrial calcium uniporter (MCU), full length (expressed in E. coli)Metarhizium acridumX-ray diffraction3.10 Å6C5W
Mitochondrial calcium uniporter (MCU), full length (expressed in Komagataella pastoris)Cyphellophora europaeaCryo-EM single particle analysis3.20 Å6DNF
Mitochondrial calcium uniporter (MCU) in complex with EMRE (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.80 Å6O58
Mitochondrial calcium uniporter holocomplex in low Ca2+ (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.20 Å6WDN
Mitochondrial calcium uniporter (MCU) holocomplex (uniplex) in nanodiscs, high calcium state (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis4.17 Å6XJV
Mitochondrial calcium uniporter (MCU) in complex with MICU1/MICU2 subunits (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.60 Å6K7Y
RyR2 ryanodine receptor, PKA phosphorylated in the closed state (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.11 Å7U9Q

Table 1. Structural Research of Calcium Ion-Selective Channels.

At Creative Biostructure, we are committed to providing high-quality structural analysis services and expertise to help our clients advance their research and achieve their scientific goals. Our team of experienced scientists has extensive expertise in X-ray crystallography, cryo-EM, NMR spectroscopy and other structural biology techniques, and we use first-class equipment and software to obtain high-resolution structures of our client's target proteins.

In general, our structural analysis services include protein expression and purification, structure determination using X-ray crystallography or cryo-EM, and structure validation and refinement. We also offer additional services, such as ligand binding studies and functional assays, to provide a comprehensive understanding of the structure and function of target proteins.

If you are interested in learning more about our structural analysis services for calcium ion-selective channels or other membrane proteins, please don't hesitate to contact us. Our team of experts will be happy to discuss your project and provide a customized solution to meet your needs.

References

  1. Zhao Y, et al. Molecular basis for ligand modulation of a mammalian voltage-gated Ca2+ channel. Cell. 2019, 177(6): 1495-1506. e12.
  2. Gao Y, et al. Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2. 3. Nature Communications. 2023, 14(1): 516.
  3. Schmitz E A, Takahashi H, Karakas E. Structural basis for activation and gating of IP3 receptors. Nature Communications. 2022, 13(1): 1408.

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