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Yorodumi- EMDB-27906: Rabbit L-type voltage-gated calcium channel Cav1.1 in the presenc... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-27906 | |||||||||
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Title | Rabbit L-type voltage-gated calcium channel Cav1.1 in the presence of Amiodarone and 1 mM MNI-1 at 3.0 Angstrom resolution | |||||||||
Map data | calcium channel | |||||||||
Sample |
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Function / homology | Function and homology information positive regulation of muscle contraction / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / calcium ion import across plasma membrane / cellular response to caffeine / calcium channel regulator activity / regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated calcium channel activity / muscle contraction ...positive regulation of muscle contraction / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / calcium ion import across plasma membrane / cellular response to caffeine / calcium channel regulator activity / regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated calcium channel activity / muscle contraction / release of sequestered calcium ion into cytosol / T-tubule / calcium ion transmembrane transport / sarcolemma / transmembrane transporter binding / calmodulin binding / metal ion binding / plasma membrane Similarity search - Function | |||||||||
Biological species | Oryctolagus cuniculus (rabbit) / rabbit (rabbit) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
Authors | Gao S / Yao X / Yan N | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Cell / Year: 2022 Title: Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca channels. Authors: Xia Yao / Shuai Gao / Jixin Wang / Zhangqiang Li / Jian Huang / Yan Wang / Zhifei Wang / Jiaofeng Chen / Xiao Fan / Weipeng Wang / Xueqin Jin / Xiaojing Pan / Yong Yu / Armando Lagrutta / Nieng Yan / Abstract: Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate ...Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Ca channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Ca1.1 and Ca1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Ca channels. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_27906.map.gz | 78 MB | EMDB map data format | |
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Header (meta data) | emd-27906-v30.xml emd-27906.xml | 19.7 KB 19.7 KB | Display Display | EMDB header |
Images | emd_27906.png | 126.7 KB | ||
Others | emd_27906_half_map_1.map.gz emd_27906_half_map_2.map.gz | 65.3 MB 65.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-27906 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-27906 | HTTPS FTP |
-Validation report
Summary document | emd_27906_validation.pdf.gz | 838.9 KB | Display | EMDB validaton report |
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Full document | emd_27906_full_validation.pdf.gz | 838.4 KB | Display | |
Data in XML | emd_27906_validation.xml.gz | 12.7 KB | Display | |
Data in CIF | emd_27906_validation.cif.gz | 15 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27906 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27906 | HTTPS FTP |
-Related structure data
Related structure data | 8e58MC 8e56C 8e57C 8e59C 8e5aC 8e5bC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_27906.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | calcium channel | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.114 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Half Map 1
File | emd_27906_half_map_1.map | ||||||||||||
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Annotation | Half Map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half Map 2
File | emd_27906_half_map_2.map | ||||||||||||
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Annotation | Half Map 2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Cav1.1
Entire | Name: Cav1.1 |
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Components |
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-Supramolecule #1: Cav1.1
Supramolecule | Name: Cav1.1 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Oryctolagus cuniculus (rabbit) |
-Macromolecule #1: Voltage-dependent L-type calcium channel subunit alpha-1S
Macromolecule | Name: Voltage-dependent L-type calcium channel subunit alpha-1S type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: rabbit (rabbit) |
Molecular weight | Theoretical: 212.240594 KDa |
Sequence | String: MEPSSPQDEG LRKKQPKKPL PEVLPRPPRA LFCLTLQNPL RKACISIVEW KPFETIILLT IFANCVALAV YLPMPEDDNN SLNLGLEKL EYFFLTVFSI EAAMKIIAYG FLFHQDAYLR SGWNVLDFII VFLGVFTAIL EQVNVIQSNT APMSSKGAGL D VKALRAFR ...String: MEPSSPQDEG LRKKQPKKPL PEVLPRPPRA LFCLTLQNPL RKACISIVEW KPFETIILLT IFANCVALAV YLPMPEDDNN SLNLGLEKL EYFFLTVFSI EAAMKIIAYG FLFHQDAYLR SGWNVLDFII VFLGVFTAIL EQVNVIQSNT APMSSKGAGL D VKALRAFR VLRPLRLVSG VPSLQVVLNS IFKAMLPLFH IALLVLFMVI IYAIIGLELF KGKMHKTCYY IGTDIVATVE NE KPSPCAR TGSGRPCTIN GSECRGGWPG PNHGITHFDN FGFSMLTVYQ CITMEGWTDV LYWVNDAIGN EWPWIYFVTL ILL GSFFIL NLVLGVLSGE FTKEREKAKS RGTFQKLREK QQLEEDLRGY MSWITQGEVM DVEDLREGKL SLEEGGSDTE SLYE IEGLN KIIQFIRHWR QWNRVFRWKC HDLVKSRVFY WLVILIVALN TLSIASEHHN QPLWLTHLQD IANRVLLSLF TIEML LKMY GLGLRQYFMS IFNRFDCFVV CSGILELLLV ESGAMTPLGI SVLRCIRLLR LFKITKYWTS LSNLVASLLN SIRSIA SLL LLLFLFIIIF ALLGMQLFGG RYDFEDTEVR RSNFDNFPQA LISVFQVLTG EDWNSVMYNG IMAYGGPSYP GVLVCIY FI ILFVCGNYIL LNVFLAIAVD NLAEAESLTS AQKAKAEERK RRKMSRGLPD KTEEEKSVMA KKLEQKPKGE GIPTTAKL K VDEFESNVNE VKDPYPSADF PGDDEEDEPE IPVSPRPRPL AELQLKEKAV PIPEASSFFI FSPTNKVRVL CHRIVNATW FTNFILLFIL LSSAALAAED PIRAESVRNQ ILGYFDIAFT SVFTVEIVLK MTTYGAFLHK GSFCRNYFNI LDLLVVAVSL ISMGLESST ISVVKILRVL RVLRPLRAIN RAKGLKHVVQ CVFVAIRTIG NIVLVTTLLQ FMFACIGVQL FKGKFFSCND L SKMTEEEC RGYYYVYKDG DPTQMELRPR QWIHNDFHFD NVLSAMMSLF TVSTFEGWPQ LLYRAIDSNE EDMGPVYNNR VE MAIFFII YIILIAFFMM NIFVGFVIVT FQEQGETEYK NCELDKNQRQ CVQYALKARP LRCYIPKNPY QYQVWYVVTS SYF EYLMFA LIMLNTICLG MQHYHQSEEM NHISDILNVA FTIIFTLEMI LKLLAFKARG YFGDPWNVFD FLIVIGSIID VILS EIDTF LASSGGLYCL GGGCGNVDPD ESARISSAFF RLFRVMRLIK LLSRAEGVRT LLWTFIKSFQ ALPYVALLIV MLFFI YAVI GMQMFGKIAL VDGTQINRNN NFQTFPQAVL LLFRCATGEA WQEILLACSY GKLCDPESDY APGEEYTCGT NFAYYY FIS FYMLCAFLII NLFVAVIMDN FDYLTRDWSI LGPHHLDEFK AIWAEYDPEA KGRIKHLDVV TLLRRIQPPL GFGKFCP HR VACKRLVGMN MPLNSDGTVT FNATLFALVR TALKIKTEGN FEQANEELRA IIKKIWKRTS MKLLDQVIPP IGDDEVTV G KFYATFLIQE HFRKFMKRQE EYYGYRPKKD TVQIQAGLRT IEEEAAPEIR RTISGDLTAE EELERAMVEA AMEERIFRR TGGLFGQVDT FLERTNSLPP VMANQRPLQF AEIEMEELES PVFLEDFPQD ARTNPLARAN TNNANANVAY GNSNHSNNQM FSSVHCERE FPGEAETPAA GRGALSHSHR ALGPHSKPCA GKLNGQLVQP GMPINQAPPA PCQQPSTDPP ERGQRRTSLT G SLQDEAPQ RRSSEGSTPR RPAPATALLI QEALVRGGLD TLAADAGFVT ATSQALADAC QMEPEEVEVA ATELLKARES VQ GMASVPG SLSRRSSLGS LDQVQGSQET LIPPRP |
-Macromolecule #2: Voltage-dependent calcium channel gamma-1 subunit
Macromolecule | Name: Voltage-dependent calcium channel gamma-1 subunit / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: rabbit (rabbit) |
Molecular weight | Theoretical: 25.082254 KDa |
Sequence | String: MSPTEAPKVR VTLFCILVGI VLAMTAVVSD HWAVLSPHME NHNTTCEAAH FGLWRICTKR IALGEDRSCG PITLPGEKNC SYFRHFNPG ESSEIFEFTT QKEYSISAAA ISVFSLGFLI MGTICALMAF RKKRDYLLRP ASMFYVFAGL CLFVSLEVMR Q SVKRMIDS ...String: MSPTEAPKVR VTLFCILVGI VLAMTAVVSD HWAVLSPHME NHNTTCEAAH FGLWRICTKR IALGEDRSCG PITLPGEKNC SYFRHFNPG ESSEIFEFTT QKEYSISAAA ISVFSLGFLI MGTICALMAF RKKRDYLLRP ASMFYVFAGL CLFVSLEVMR Q SVKRMIDS EDTVWIEYYY SWSFACACAA FVLLFLGGIS LLLFSLPRMP QNPWESCMDA EPEH |
-Macromolecule #3: Voltage-dependent calcium channel subunit alpha-2/delta-1
Macromolecule | Name: Voltage-dependent calcium channel subunit alpha-2/delta-1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: rabbit (rabbit) |
Molecular weight | Theoretical: 125.169984 KDa |
Sequence | String: MAAGRPLAWT LTLWQAWLIL IGPSSEEPFP SAVTIKSWVD KMQEDLVTLA KTASGVHQLV DIYEKYQDLY TVEPNNARQL VEIAARDIE KLLSNRSKAL VRLALEAEKV QAAHQWREDF ASNEVVYYNA KDDLDPEKND SEPGSQRIKP VFIDDANFRR Q VSYQHAAV ...String: MAAGRPLAWT LTLWQAWLIL IGPSSEEPFP SAVTIKSWVD KMQEDLVTLA KTASGVHQLV DIYEKYQDLY TVEPNNARQL VEIAARDIE KLLSNRSKAL VRLALEAEKV QAAHQWREDF ASNEVVYYNA KDDLDPEKND SEPGSQRIKP VFIDDANFRR Q VSYQHAAV HIPTDIYEGS TIVLNELNWT SALDDVFKKN REEDPSLLWQ VFGSATGLAR YYPASPWVDN SRTPNKIDLY DV RRRPWYI QGAASPKDML ILVDVSGSVS GLTLKLIRTS VSEMLETLSD DDFVNVASFN SNAQDVSCFQ HLVQANVRNK KVL KDAVNN ITAKGITDYK KGFSFAFEQL LNYNVSRANC NKIIMLFTDG GEERAQEIFA KYNKDKKVRV FTFSVGQHNY DRGP IQWMA CENKGYYYEI PSIGAIRINT QEYLDVLGRP MVLAGDKAKQ VQWTNVYLDA LELGLVITGT LPVFNITGQF ENKTN LKNQ LILGVMGVDV SLEDIKRLTP RFTLCPNGYY FAIDPNGYVL LHPNLQPKPI GVGIPTINLR KRRPNVQNPK SQEPVT LDF LDAELENDIK VEIRNKMIDG ESGEKTFRTL VKSQDERYID KGNRTYTWTP VNGTDYSSLA LVLPTYSFYY IKAKIEE TI TQARYSETLK PDNFEESGYT FLAPRDYCSD LKPSDNNTEF LLNFNEFIDR KTPNNPSCNT DLINRVLLDA GFTNELVQ N YWSKQKNIKG VKARFVVTDG GITRVYPKEA GENWQENPET YEDSFYKRSL DNDNYVFTAP YFNKSGPGAY ESGIMVSKA VEIYIQGKLL KPAVVGIKID VNSWIENFTK TSIRDPCAGP VCDCKRNSDV MDCVILDDGG FLLMANHDDY TNQIGRFFGE IDPSLMRHL VNISVYAFNK SYDYQSVCEP GAAPKQGAGH RSAYVPSIAD ILQIGWWATA AAWSILQQFL LSLTFPRLLE A ADMEDDDF TASMSKQSCI TEQTQYFFDN DSKSFSGVLD CGNCSRIFHV EKLMNTNLIF IMVESKGTCP CDTRLLIQAE QT SDGPDPC DMVKQPRYRK GPDVCFDNNV LEDYTDCGGV SGLNPSLWSI IGIQFVLLWL VSGSRHCLL |
-Macromolecule #7: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 2 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #8: (2-butyl-1-benzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5-diiodo...
Macromolecule | Name: (2-butyl-1-benzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl}methanone type: ligand / ID: 8 / Number of copies: 1 / Formula: BBI |
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Molecular weight | Theoretical: 645.312 Da |
Chemical component information | ChemComp-BBI: |
-Macromolecule #9: propan-2-yl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro...
Macromolecule | Name: propan-2-yl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-3-hydroxy-4-methyloxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (non-preferred name) type: ligand / ID: 9 / Number of copies: 1 / Formula: WFR |
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Molecular weight | Theoretical: 535.483 Da |
Chemical component information | ChemComp-WFR: |
-Macromolecule #10: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 10 / Number of copies: 7 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 83355 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |