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- EMDB-29609: Cryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-... -

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Basic information

Entry
Database: EMDB / ID: EMD-29609
TitleCryo-EM map of chimeric Sec complex (human Sec61 and yeast Sec63-71-72) inhibited by cotransin
Map dataUnsharpened map for cotransin bound chimeric Sec complex (whole).
Sample
  • Complex: A human-yeast chimeric Sec complex treated with cotransin
    • Protein or peptide: Protein transport protein Sec61 subunit gamma
    • Protein or peptide: Protein transport protein Sec61 subunit beta
    • Protein or peptide: Protein transport protein Sec61 subunit alpha isoform 1
    • Protein or peptide: Protein transport protein Sec71
    • Protein or peptide: Protein transport protein Sec72
    • Protein or peptide: Protein transport protein Sec63, yeast-human chimera
Keywordstranslocon / inhibitor / protein translocation / PROTEIN TRANSPORT / PROTEIN TRANSPORT-INHIBITOR complex
Function / homology
Function and homology information


Sec62/Sec63 complex / translocon complex / cytosol to endoplasmic reticulum transport / endoplasmic reticulum Sec complex / pronephric nephron development / rough endoplasmic reticulum membrane / endoplasmic reticulum quality control compartment / cotranslational protein targeting to membrane / Ssh1 translocon complex / Sec61 translocon complex ...Sec62/Sec63 complex / translocon complex / cytosol to endoplasmic reticulum transport / endoplasmic reticulum Sec complex / pronephric nephron development / rough endoplasmic reticulum membrane / endoplasmic reticulum quality control compartment / cotranslational protein targeting to membrane / Ssh1 translocon complex / Sec61 translocon complex / protein targeting to ER / protein insertion into ER membrane / post-translational protein targeting to endoplasmic reticulum membrane / filamentous growth / SRP-dependent cotranslational protein targeting to membrane, translocation / SRP-dependent cotranslational protein targeting to membrane / signal sequence binding / post-translational protein targeting to membrane, translocation / endoplasmic reticulum organization / nuclear inner membrane / epidermal growth factor binding / retrograde protein transport, ER to cytosol / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / protein transmembrane transporter activity / SRP-dependent cotranslational protein targeting to membrane / ERAD pathway / guanyl-nucleotide exchange factor activity / cell periphery / calcium channel activity / ribosome binding / ER-Phagosome pathway / endoplasmic reticulum membrane / endoplasmic reticulum / mitochondrion / RNA binding / membrane / cytosol
Similarity search - Function
Translocation protein Sec66 / Preprotein translocase subunit Sec66 / Protein transport Sec61-beta/Sbh / Protein transport protein SecG/Sec61-beta/Sbh / Sec61beta family / Protein translocase SEC61 complex, gamma subunit / Protein translocase SecE domain superfamily / Translocon Sec61/SecY, plug domain / Plug domain of Sec61p / Nt-dnaJ domain signature. ...Translocation protein Sec66 / Preprotein translocase subunit Sec66 / Protein transport Sec61-beta/Sbh / Protein transport protein SecG/Sec61-beta/Sbh / Sec61beta family / Protein translocase SEC61 complex, gamma subunit / Protein translocase SecE domain superfamily / Translocon Sec61/SecY, plug domain / Plug domain of Sec61p / Nt-dnaJ domain signature. / DnaJ domain, conserved site / Protein secE/sec61-gamma signature. / Protein secY signature 1. / Protein secY signature 2. / SecE/Sec61-gamma subunits of protein translocation complex / Protein translocase complex, SecE/Sec61-gamma subunit / SecY/SEC61-alpha family / SecY domain superfamily / SecY conserved site / SecY / DnaJ domain / Sec63 domain / Sec63 Brl domain / DnaJ molecular chaperone homology domain / dnaJ domain profile. / Chaperone J-domain superfamily / DnaJ domain / Tetratricopeptide repeats / Tetratricopeptide repeat / Tetratricopeptide-like helical domain superfamily / Immunoglobulin E-set
Similarity search - Domain/homology
Protein translocation protein SEC63 / Translocation protein SEC66 / Translocation protein SEC72 / Protein transport protein Sec61 subunit gamma / Protein transport protein Sec61 subunit beta / Protein transport protein Sec61 subunit alpha isoform 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Saccharomyces cerevisiae (brewer's yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsPark E / Itskanov S
Funding support United States, 2 items
OrganizationGrant numberCountry
The Vallee Foundation Inc. United States
The Pew Charitable Trusts United States
CitationJournal: Nat Chem Biol / Year: 2023
Title: A common mechanism of Sec61 translocon inhibition by small molecules.
Authors: Samuel Itskanov / Laurie Wang / Tina Junne / Rumi Sherriff / Li Xiao / Nicolas Blanchard / Wei Q Shi / Craig Forsyth / Dominic Hoepfner / Martin Spiess / Eunyong Park /
Abstract: The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural ...The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design.
History
DepositionJan 28, 2023-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateSep 6, 2023-
Current statusSep 6, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29609.png

Downloads & links

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Map

FileDownload / File: emd_29609.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationUnsharpened map for cotransin bound chimeric Sec complex (whole).
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 256 pix.
= 268.8 Å		1.05 Å/pix.
x 256 pix.
= 268.8 Å		1.05 Å/pix.
x 256 pix.
= 268.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.27143088 - 0.8983025
Average (Standard dev.)0.0037787643 (±0.027521431)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 268.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Sharpened map for cotransin bound chimeric Sec complex (whole).

Fileemd_29609_additional_1.map
AnnotationSharpened map for cotransin bound chimeric Sec complex (whole).
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B for cotransin bound chimeric Sec complex (whole).

Fileemd_29609_half_map_1.map
AnnotationHalf map B for cotransin bound chimeric Sec complex (whole).
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A for cotransin bound chimeric Sec complex (whole).

Fileemd_29609_half_map_2.map
AnnotationHalf map A for cotransin bound chimeric Sec complex (whole).
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : A human-yeast chimeric Sec complex treated with cotransin

EntireName: A human-yeast chimeric Sec complex treated with cotransin
Components
  • Complex: A human-yeast chimeric Sec complex treated with cotransin
    • Protein or peptide: Protein transport protein Sec61 subunit gamma
    • Protein or peptide: Protein transport protein Sec61 subunit beta
    • Protein or peptide: Protein transport protein Sec61 subunit alpha isoform 1
    • Protein or peptide: Protein transport protein Sec71
    • Protein or peptide: Protein transport protein Sec72
    • Protein or peptide: Protein transport protein Sec63, yeast-human chimera

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Supramolecule #1: A human-yeast chimeric Sec complex treated with cotransin

SupramoleculeName: A human-yeast chimeric Sec complex treated with cotransin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organelle: endoplasmic reticulum

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Macromolecule #1: Protein transport protein Sec61 subunit gamma

MacromoleculeName: Protein transport protein Sec61 subunit gamma / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MDQVMQFVEP SRQFVKDSIR LVKRCTKPDR KEFQKIAMAT AIGFAIMGFI GFFVKLIHIP INNIIVGG

UniProtKB: Protein transport protein Sec61 subunit gamma

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Macromolecule #2: Protein transport protein Sec61 subunit beta

MacromoleculeName: Protein transport protein Sec61 subunit beta / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MPGPTPSGTN VGSSGRSPSK AVAARAAGST VRQRKNASCG TRSAGRTTSA GTGGMWRFYT EDSPGLKVGP VPVLVMSLLF IASVFMLHI WGKYTRS

UniProtKB: Protein transport protein Sec61 subunit beta

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Macromolecule #3: Protein transport protein Sec61 subunit alpha isoform 1

MacromoleculeName: Protein transport protein Sec61 subunit alpha isoform 1
type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAIKFLEVIK PFCVILPEIQ KPERKIQFKE KVLWTAITLF IFLVCCQIPL FGIMSSDSAD PFYWMRVILA SNRGTLMELG ISPIVTSGL IMQLLAGAKI IEVGDTPKDR ALFNGAQKLF GMIITIGQSI VYVMTGMYGD PSEMGAGICL LITIQLFVAG L IVLLLDEL ...String:
MAIKFLEVIK PFCVILPEIQ KPERKIQFKE KVLWTAITLF IFLVCCQIPL FGIMSSDSAD PFYWMRVILA SNRGTLMELG ISPIVTSGL IMQLLAGAKI IEVGDTPKDR ALFNGAQKLF GMIITIGQSI VYVMTGMYGD PSEMGAGICL LITIQLFVAG L IVLLLDEL LQKGYGLGSG ISLFIATNIC ETIVWKAFSP TTVNTGRGME FEGAIIALFH LLATRTDKVR ALREAFYRQN LP NLMNLIA TIFVFAVVIY FQGFRYELPI RSTKVRGQIG IYPIKLFYTS NIPIILQSAL VSNLYVISQM LSARFSGNLL VSL LGTWSD TSSGGPARAY PVGGLCYYLS PPESFGSVLE DPVHAVVYIV FMLGSCAFFS KTWIEVSGSS PRDIAKQFKD QGMV INGKR ETSIYRELKK IIPTAAAFGG LCIGALSVLA DFLGAIGSGT GILLAVTIIY QYFEIFVKEQ SEVGSMGALL F

UniProtKB: Protein transport protein Sec61 subunit alpha isoform 1

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Macromolecule #4: Protein transport protein Sec71

MacromoleculeName: Protein transport protein Sec71 / type: protein_or_peptide / ID: 4 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSEFNETKFS NNGTFFETEE PIVETKSISV YTPLIYVFIL VVSLVMFASS YRKKQAKKIS EQPSIFDEND AHDLYFQIKE MSENEKIHEK VLKAALLNRG AESVRRSLKL KELAPQINLL YKNGSIGEDY WKRFETEVKL IELEFKDTLQ EAERLQPGWV QLFVMVCKEI ...String:
MSEFNETKFS NNGTFFETEE PIVETKSISV YTPLIYVFIL VVSLVMFASS YRKKQAKKIS EQPSIFDEND AHDLYFQIKE MSENEKIHEK VLKAALLNRG AESVRRSLKL KELAPQINLL YKNGSIGEDY WKRFETEVKL IELEFKDTLQ EAERLQPGWV QLFVMVCKEI CFNQALSRRY QSILKRKEVC IKEWELKINN DGRLVN

UniProtKB: Translocation protein SEC66

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Macromolecule #5: Protein transport protein Sec72

MacromoleculeName: Protein transport protein Sec72 / type: protein_or_peptide / ID: 5 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MVTLEYNANS KLITASDAVV ALSTETNIDQ INVLTTSLIG ETNPNFTPQP NEALSKMIKG LFESGMKNLQ QKKLNEALKN VSLAIEMAQR KRAPWEAFAI QLPELHFMLR SKIDLCLILG KHLEALQDLD FLLGTGLIQP DVFVRKADCL LKLRQWEEAR ATCERGLALA PEDMKLRALL IETARNLAEY NGE

UniProtKB: Translocation protein SEC72

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Macromolecule #6: Protein transport protein Sec63, yeast-human chimera

MacromoleculeName: Protein transport protein Sec63, yeast-human chimera / type: protein_or_peptide / ID: 6 / Enantiomer: LEVO
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString: MAGQQFQYDD SGNTFFYFLT SFVGLIVIPM TLLQIYQIFF GANAEDGNSG KSKEFNEEVF KNLNEEYTSD EIKQFRRKFD KNSNKKSKIW SRRNIVLLAG WALFLFLAYK VSKTDREYQE YNPYEVLNLD PGATVAEIKK QYRLLSLKYH PDKGGDEVMF MRIAKAYAAL ...String:
MAGQQFQYDD SGNTFFYFLT SFVGLIVIPM TLLQIYQIFF GANAEDGNSG KSKEFNEEVF KNLNEEYTSD EIKQFRRKFD KNSNKKSKIW SRRNIVLLAG WALFLFLAYK VSKTDREYQE YNPYEVLNLD PGATVAEIKK QYRLLSLKYH PDKGGDEVMF MRIAKAYAAL TDEESRKNWE EFGNPDGPQA TSFGIALPAW IVDQKNSILV LLVYGLAFMV ILPVVVGSWW YRTQSYTKKG IHNVTASNFV SNLVNYKPSE IVTTDLILHW LSFAHEFKQF FPDLQPTDFE KLLQDHINRR DSGKLNNAKF RIVAKCHSLL HGLLDIACGF RNLDIALGAI NTFKCIVQAV PLTPNCQILQ LPNVDKEHFI TKTGDIHTLG KLFTLEDAKI GEVLGIKDQA KLNETLRVAS HIPNLKIIKA DFLVPGENQV TPSSTPYISL KVLVRSAKQP LIPTSLIPEE NLTEPQDFES QRDPFAMMSK QPLVPYSFAP FFPTKRRGSW CCLVSSQKDG KILQTPIIIE KLSYKNLNDD KDFFDKRIKM DLTKHEKFDI NDWEIGTIKI PLGQPAPETV GDFFFRVIVK STDYFTTDLD ITMNMKVRDS PAVEQVEVYS EEDDEYSTDD DETESDDESD ASDYTDIDTD TEAEDDESPE GAGSNSLEVL FQ

UniProtKB: Protein translocation protein SEC63

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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

Concentration10 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mM(HOCH2)3CNH2Tris
100.0 mMNaClsodium chloride
2.0 mMC4H10O2S2dithiothreitol
1.0 mMC10H16N2O8EDTA
3.0 mMC13H17F13NO4PFluorinated Fos-choline-8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 35 sec. / Pretreatment - Atmosphere: AIR / Details: Used a PELCO easiGlow glow discharge cleaner
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: blot for 4 seconds before plunging.
DetailsReconsitituted into a peptidisc. Monodisperse peak from a Superose 6 column.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k 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 / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 274970
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3) / Number images used: 137441
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3)

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