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- EMDB-28530: Human R-type voltage-gated calcium channel Cav2.3 CH2II-deleted m... -

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Basic information

Entry
Database: EMDB / ID: EMD-28530
TitleHuman R-type voltage-gated calcium channel Cav2.3 CH2II-deleted mutant at 3.1 Angstrom resolution
Map datacalcium channel mutation
Sample
  • Complex: Cav2.3
    • Protein or peptide: Voltage-dependent R-type calcium channel subunit alpha-1E
    • Protein or peptide: Voltage-dependent calcium channel subunit alpha-2/delta-1
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsCav2.3 / Channels / Calcium Ion-Selective / TRANSPORT PROTEIN
Function / homology
Function and homology information


regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / cardiac muscle cell action potential involved in contraction / regulation of ventricular cardiac muscle cell membrane repolarization / voltage-gated monoatomic cation channel activity ...regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / cardiac muscle cell action potential involved in contraction / regulation of ventricular cardiac muscle cell membrane repolarization / voltage-gated monoatomic cation channel activity / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / calcium ion import across plasma membrane / neuronal dense core vesicle / regulation of heart rate by cardiac conduction / regulation of calcium ion transport / voltage-gated calcium channel activity / sarcoplasmic reticulum / Regulation of insulin secretion / cellular response to amyloid-beta / calcium ion transport / chemical synaptic transmission / neuronal cell body / calcium ion binding / synapse / extracellular exosome / metal ion binding / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, R-type, alpha-1 subunit / VWA N-terminal / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / : / VWA N-terminal / Neuronal voltage-dependent calcium channel alpha 2acd / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain / : / Voltage gated calcium channel IQ domain / Voltage gated calcium channel IQ domain ...Voltage-dependent calcium channel, R-type, alpha-1 subunit / VWA N-terminal / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / : / VWA N-terminal / Neuronal voltage-dependent calcium channel alpha 2acd / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain / : / Voltage gated calcium channel IQ domain / Voltage gated calcium channel IQ domain / Voltage-dependent calcium channel, alpha-1 subunit / Voltage-dependent L-type calcium channel, IQ-associated domain / Voltage-dependent L-type calcium channel, IQ-associated / von Willebrand factor type A domain / von Willebrand factor (vWF) type A domain / VWFA domain profile. / Voltage-dependent channel domain superfamily / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent R-type calcium channel subunit alpha-1E
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsGao S / Yao X / Yan N
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM130762 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)7R01GM057440-19 United States
CitationJournal: Nat Commun / Year: 2022
Title: Structures of the R-type human Ca2.3 channel reveal conformational crosstalk of the intracellular segments.
Authors: Xia Yao / Yan Wang / Zhifei Wang / Xiao Fan / Di Wu / Jian Huang / Alexander Mueller / Sarah Gao / Miaohui Hu / Carol V Robinson / Yong Yu / Shuai Gao / Nieng Yan /
Abstract: The R-type voltage-gated Ca (Ca) channels Ca2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson's disease. Despite ...The R-type voltage-gated Ca (Ca) channels Ca2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson's disease. Despite their physiological importance, there have lacked selective small-molecule inhibitors targeting these channels. High-resolution structures may aid rational drug design. Here, we report the cryo-EM structure of human Ca2.3 in complex with α2δ-1 and β3 subunits at an overall resolution of 3.1 Å. The structure is nearly identical to that of Ca2.2, with VSD in the down state and the other three VSDs up. A phosphatidylinositol 4,5-bisphosphate (PIP2) molecule binds to the interface of VSD and the tightly closed pore domain. We also determined the cryo-EM structure of a Ca2.3 mutant in which a Ca2-unique cytosolic helix in repeat II (designated the CH2 helix) is deleted. This mutant, named ΔCH2, still reserves a down VSD, but PIP2 is invisible and the juxtamembrane region on the cytosolic side is barely discernible. Our structural and electrophysiological characterizations of the wild type and ΔCH2 Ca2.3 show that the CH2 helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments, while CH2 helix is not necessary for locking the down state of VSD.
History
DepositionOct 6, 2022-
Header (metadata) releaseDec 14, 2022-
Map releaseDec 14, 2022-
UpdateJul 12, 2023-
Current statusJul 12, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28530.png

Downloads & links

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Map

FileDownload / File: emd_28530.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcalcium channel mutation
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.11 Å/pix.
x 280 pix.
= 311.92 Å		1.11 Å/pix.
x 280 pix.
= 311.92 Å		1.11 Å/pix.
x 280 pix.
= 311.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.114 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.09868589 - 0.16633105
Average (Standard dev.)-0.000013777313 (±0.0050409376)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 311.91998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_28530_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_28530_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cav2.3

EntireName: Cav2.3
Components
  • Complex: Cav2.3
    • Protein or peptide: Voltage-dependent R-type calcium channel subunit alpha-1E
    • Protein or peptide: Voltage-dependent calcium channel subunit alpha-2/delta-1
  • Ligand: CALCIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Cav2.3

SupramoleculeName: Cav2.3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Voltage-dependent R-type calcium channel subunit alpha-1E

MacromoleculeName: Voltage-dependent R-type calcium channel subunit alpha-1E
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 262.055984 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MARFGEAVVA RPGSGDGDSD QSRNRQGTPV PASGQAAAYK QTKAQRARTM ALYNPIPVRQ NCFTVNRSLF IFGEDNIVRK YAKKLIDWP PFEYMILATI IANCIVLALE QHLPEDDKTP MSRRLEKTEP YFIGIFCFEA GIKIVALGFI FHKGSYLRNG W NVMDFIVV ...String:
MARFGEAVVA RPGSGDGDSD QSRNRQGTPV PASGQAAAYK QTKAQRARTM ALYNPIPVRQ NCFTVNRSLF IFGEDNIVRK YAKKLIDWP PFEYMILATI IANCIVLALE QHLPEDDKTP MSRRLEKTEP YFIGIFCFEA GIKIVALGFI FHKGSYLRNG W NVMDFIVV LSGILATAGT HFNTHVDLRT LRAVRVLRPL KLVSGIPSLQ IVLKSIMKAM VPLLQIGLLL FFAILMFAII GL EFYSGKL HRACFMNNSG ILEGFDPPHP CGVQGCPAGY ECKDWIGPND GITQFDNILF AVLTVFQCIT MEGWTTVLYN TND ALGATW NWLYFIPLII IGSFFVLNLV LGVLSGEFAK ERERVENRRA FMKLRRQQQI ERELNGYRAW IDKAEEVMLA EENK NAGTS ALEVLRRATI KRSRTEAMTR DSSDEHCVDI SSVGTPLARA SIKSAKVDGV SYFRHKERLL RISIRHMVKS QVFYW IVLS LVALNTACVA IVHHNQPQWL THLLYYAEFL FLGLFLLEMS LKMYGMGPRL YFHSSFNCFD FGVTVGSIFE VVWAIF RPG TSFGISVLRA LRLLRIFKIT KYWASLRNLV VSLMSSMKSI ISLLFLLFLF IVVFALLGMQ LFGGRFNFND GTPSANF DT FPAAIMTVFQ ILTGEDWNEV MYNGIRSQGG VSSGMWSAIY FIVLTLFGNY TLLNVFLAIA VDNLANAQEL TKDEQEEE E AFNQKHALQK AKEVSPMSAP NMPSIERDRR RRHHMSMWEP RSSHLRERRR RHHMSVWEQR TSQLRKHMQM SSQEALNRE EAPTMNPLNP LNPLSSLNPL NAHPSLYRRP RAIEGLALGL ALEKFEEERI SRGGSLKGDG GDRSSALDNQ RTPLSLGQRE PPWLARPCH GNCDPTQQEA GGGEAVVTFE DRARHRQSQR RSRHRRVRTE GKESSSASRS RSASQERSLD EAMPTEGEKD H ELRGNHGA KEPTIQEERA QDLRRTNSLM VSRGSGLAGG LDEADTPLVL PHPELEVGKH VVLTEQEPEG SSEQALLGNV QL DMGRVIS QSEPDLSCIT ANTDKATTES TSVTVAIPDV DPLVDSTVVH ISNKTDGEAS PLKEAEIRED EEEVEKKKQK KEK RETGKA MVPHSSMFIF STTNPIRRAC HYIVNLRYFE MCILLVIAAS SIALAAEDPV LTNSERNKVL RYFDYVFTGV FTFE MVIKM IDQGLILQDG SYFRDLWNIL DFVVVVGALV AFALANALGT NKGRDIKTIK SLRVLRVLRP LKTIKRLPKL KAVFD CVVT SLKNVFNILI VYKLFMFIFA VIAVQLFKGK FFYCTDSSKD TEKECIGNYV DHEKNKMEVK GREWKRHEFH YDNIIW ALL TLFTVSTGEG WPQVLQHSVD VTEEDRGPSR SNRMEMSIFY VVYFVVFPFF FVNIFVALII ITFQEQGDKM MEECSLE KN ERACIDFAIS AKPLTRYMPQ NRHTFQYRVW HFVVSPSFEY TIMAMIALNT VVLMMKYYSA PCTYELALKY LNIAFTMV F SLECVLKVIA FGFLNYFRDT WNIFDFITVI GSITEIILTD SKLVNTSGFN MSFLKLFRAA RLIKLLRQGY TIRILLWTF VQSFKALPYV CLLIAMLFFI YAIIGMQVFG NIKLDEESHI NRHNNFRSFF GSLMLLFRSA TGEAWQEIML SCLGEKGCEP DTTAPSGQN ENERCGTDLA YVYFVSFIFF CSFLMLNLFV AVIMDNFEYL TRDSSILGPH HLDEFVRVWA EYDRAACGRI H YTEMYEML TLMSPPLGLG KRCPSKVAYK RLVLMNMPVA EDMTVHFTST LMALIRTALD IKIAKGGADR QQLDSELQKE TL AIWPHLS QKMLDLLVPM PKASDLTVGK IYAAMMIMDY YKQSKVKKQR QQLEEQKNAP MFQRMEPSSL PQEIIANAKA LPY LQQDPV SGLSGRSGYP SMSPLSPQDI FQLACMDPAD DGQFQERQSL EPEVSELKSV QPSNHGIYLP SDTQEHAGSG RASS MPRLT VDPQVVTDPS SMRRSFSTIR DKRSNSSWLE EFSMERSSEN TYKSRRRSYH SSLRLSAHRL NSDSGHKSDT HRSGG RERG RSKERKHLLS PDVSRCNSEE RGTQADWESP ERRQSRSPSE GRSQTPNRQG TGSLSESSIP SVSDTSTPRR SRRQLP PVP PKPRPLLSYS SLIRHAGSIS PPADGSEEGS PLTSQALESN NACLTESSNS PHPQQSQHAS PQRYISEPYL ALHEDSH AS DCGEEETLTF EAAVATSLGR SNTIGSAPPL RHSWQMPNGH YRRRRRGGPG PGMMCGAVNN LLSDTEEDDK C

UniProtKB: Voltage-dependent R-type calcium channel subunit alpha-1E

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Macromolecule #2: Voltage-dependent calcium channel subunit alpha-2/delta-1

MacromoleculeName: Voltage-dependent calcium channel subunit alpha-2/delta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 124.692469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAGCLLALT LTLFQSLLIG PSSEEPFPSA VTIKSWVDKM QEDLVTLAKT ASGVNQLVDI YEKYQDLYTV EPNNARQLVE IAARDIEKL LSNRSKALVR LALEAEKVQA AHQWREDFAS NEVVYYNAKD DLDPEKNDSE PGSQRIKPVF IEDANFGRQI S YQHAAVHI ...String:
MAAGCLLALT LTLFQSLLIG PSSEEPFPSA VTIKSWVDKM QEDLVTLAKT ASGVNQLVDI YEKYQDLYTV EPNNARQLVE IAARDIEKL LSNRSKALVR LALEAEKVQA AHQWREDFAS NEVVYYNAKD DLDPEKNDSE PGSQRIKPVF IEDANFGRQI S YQHAAVHI PTDIYEGSTI VLNELNWTSA LDEVFKKNRE EDPSLLWQVF GSATGLARYY PASPWVDNSR TPNKIDLYDV RR RPWYIQG AASPKDMLIL VDVSGSVSGL TLKLIRTSVS EMLETLSDDD FVNVASFNSN AQDVSCFQHL VQANVRNKKV LKD AVNNIT AKGITDYKKG FSFAFEQLLN YNVSRANCNK IIMLFTDGGE ERAQEIFNKY NKDKKVRVFT FSVGQHNYDR GPIQ WMACE NKGYYYEIPS IGAIRINTQE YLDVLGRPMV LAGDKAKQVQ WTNVYLDALE LGLVITGTLP VFNITGQFEN KTNLK NQLI LGVMGVDVSL EDIKRLTPRF TLCPNGYYFA IDPNGYVLLH PNLQPKPIGV GIPTINLRKR RPNIQNPKSQ EPVTLD FLD AELENDIKVE IRNKMIDGES GEKTFRTLVK SQDERYIDKG NRTYTWTPVN GTDYSLALVL PTYSFYYIKA KLEETIT QA RYSETLKPDN FEESGYTFIA PRDYCNDLKI SDNNTEFLLN FNEFIDRKTP NNPSCNADLI NRVLLDAGFT NELVQNYW S KQKNIKGVKA RFVVTDGGIT RVYPKEAGEN WQENPETYED SFYKRSLDND NYVFTAPYFN KSGPGAYESG IMVSKAVEI YIQGKLLKPA VVGIKIDVNS WIENFTKTSI RDPCAGPVCD CKRNSDVMDC VILDDGGFLL MANHDDYTNQ IGRFFGEIDP SLMRHLVNI SVYAFNKSYD YQSVCEPGAA PKQGAGHRSA YVPSVADILQ IGWWATAAAW SILQQFLLSL TFPRLLEAVE M EDDDFTAS LSKQSCITEQ TQYFFDNDSK SFSGVLDCGN CSRIFHGEKL MNTNLIFIMV ESKGTCPCDT RLLIQAEQTS DG PNPCDMV KQPRYRKGPD VCFDNNVLED YTDCGGVSGL NPSLWYIIGI QFLLLWLVSG STHRLL

UniProtKB: Voltage-dependent calcium channel subunit alpha-2/delta-1

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 1.9000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 68109
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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