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- EMDB-14776: Signal peptide mimicry primes Sec61 for client-selective inhibition -

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Basic information

Entry
Database: EMDB / ID: EMD-14776
TitleSignal peptide mimicry primes Sec61 for client-selective inhibition
Map data
Sample
  • Complex: Protein conducting Sec61 translocon complex
    • Complex: Protein conducting Sec61 translocon complex
      • Protein or peptide: Protein transport protein Sec61 subunit alphaProtein targeting
      • Protein or peptide: Protein transport protein Sec61 subunit gammaProtein targeting
    • Complex: Signal peptide mimic
      • Protein or peptide: Cyclic depsipeptide signal peptide mimic
  • Protein or peptide: Protein transport protein Sec61 subunit betaProtein targeting
KeywordsSec61 Translocon / cryoEM / Membrane Protein / Protein biogenesis
Function / homology
Function and homology information


protein transmembrane transporter activity / protein targeting / protein transport / endoplasmic reticulum membrane
Similarity search - Function
Protein translocase SEC61 complex, gamma subunit / Protein translocase SecE domain superfamily / Translocon Sec61/SecY, plug domain / Plug domain of Sec61p / 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 ...Protein translocase SEC61 complex, gamma subunit / Protein translocase SecE domain superfamily / Translocon Sec61/SecY, plug domain / Plug domain of Sec61p / 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
Similarity search - Domain/homology
Translocon Sec61/SecY plug domain-containing protein / Protein transport protein Sec61 subunit gamma
Similarity search - Component
Biological speciesOvis aries (sheep) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsRehan S / Paavilainen O V
Funding support Finland, 1 items
OrganizationGrant numberCountry
Academy of Finland314672 Finland
CitationJournal: Nat Chem Biol / Year: 2023
Title: Signal peptide mimicry primes Sec61 for client-selective inhibition.
Authors: Shahid Rehan / Dale Tranter / Phillip P Sharp / Gregory B Craven / Eric Lowe / Janet L Anderl / Tony Muchamuel / Vahid Abrishami / Suvi Kuivanen / Nicole A Wenzell / Andy Jennings / ...Authors: Shahid Rehan / Dale Tranter / Phillip P Sharp / Gregory B Craven / Eric Lowe / Janet L Anderl / Tony Muchamuel / Vahid Abrishami / Suvi Kuivanen / Nicole A Wenzell / Andy Jennings / Chakrapani Kalyanaraman / Tomas Strandin / Matti Javanainen / Olli Vapalahti / Matthew P Jacobson / Dustin McMinn / Christopher J Kirk / Juha T Huiskonen / Jack Taunton / Ville O Paavilainen /
Abstract: Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. ...Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
History
DepositionApr 13, 2022-
Header (metadata) releaseMar 22, 2023-
Map releaseMar 22, 2023-
UpdateNov 15, 2023-
Current statusNov 15, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14776.png

Downloads & links

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Map

FileDownload / File: emd_14776.map.gz / Format: CCP4 / Size: 1.9 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)X (Row.)Y (Col.)
0.83 Å/pix.
x 800 pix.
= 664. Å		0.83 Å/pix.
x 800 pix.
= 664. Å		0.83 Å/pix.
x 800 pix.
= 664. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00275
Minimum - Maximum-0.010949552 - 0.033659477
Average (Standard dev.)0.00001483572 (±0.00089833565)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderYXZ
Origin000
Dimensions800800800
Spacing800800800
CellA=B=C: 664.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_14776_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_14776_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Protein conducting Sec61 translocon complex

EntireName: Protein conducting Sec61 translocon complex
Components
  • Complex: Protein conducting Sec61 translocon complex
    • Complex: Protein conducting Sec61 translocon complex
      • Protein or peptide: Protein transport protein Sec61 subunit alphaProtein targeting
      • Protein or peptide: Protein transport protein Sec61 subunit gammaProtein targeting
    • Complex: Signal peptide mimic
      • Protein or peptide: Cyclic depsipeptide signal peptide mimic
  • Protein or peptide: Protein transport protein Sec61 subunit betaProtein targeting

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Supramolecule #1: Protein conducting Sec61 translocon complex

SupramoleculeName: Protein conducting Sec61 translocon complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2, #4
Molecular weightTheoretical: 3.4 MDa

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Supramolecule #2: Protein conducting Sec61 translocon complex

SupramoleculeName: Protein conducting Sec61 translocon complex / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Ovis aries (sheep)

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Supramolecule #3: Signal peptide mimic

SupramoleculeName: Signal peptide mimic / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: synthetic construct (others)

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Macromolecule #1: Protein transport protein Sec61 subunit alpha

MacromoleculeName: Protein transport protein Sec61 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 52.034062 KDa
SequenceString: MGIKFLEVIK PFCVILPEIQ KPERKIQFKE KVLWTAITLF IFLVCCQIPL FGIMSSDSAD PYWMRVILAS NRGTLMALGI SPIVTSGLI MQLLAGAKII EVGDTPKDRA LFNGAQKLFG MTITIGQSIV YVMTGMYGDP SEMGAGVCLL ITIQLFVAGL I VLLLDELL ...String:
MGIKFLEVIK PFCVILPEIQ KPERKIQFKE KVLWTAITLF IFLVCCQIPL FGIMSSDSAD PYWMRVILAS NRGTLMALGI SPIVTSGLI MQLLAGAKII EVGDTPKDRA LFNGAQKLFG MTITIGQSIV YVMTGMYGDP SEMGAGVCLL ITIQLFVAGL I VLLLDELL QKGYGLGSGI SLFIATNICE TIVWKAFSPT TVNTGRGMEF EGAIIALFHL LATRTDKVRA LREAFYRQNL PN LMNLIAT IFVFAVVIYF QGFRVDLPIK SARYRGQYNT YPIKLFYTSN IPIILQSALV SNLYVISQML SARFSGNLLV SLL GTWSDT SSGGPARAYP VGGLCHYLSP PESFGSVLED PVHAVVYIVF MLGSCAFFSK TWIEVSGSSA KDVAKQLKEQ QMVM RGHRE TSMVHELNRY IPTAAAFGGL CIGALSVLAD FLGAIGSGTG ILLAVTIIYQ YFEIFVKEQS EVGSMGALLF

UniProtKB: Translocon Sec61/SecY plug domain-containing protein

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Macromolecule #2: Protein transport protein Sec61 subunit gamma

MacromoleculeName: Protein transport protein Sec61 subunit gamma / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 7.752325 KDa
SequenceString:
MDQVMQFVEP SRQFVKDSIR LVKRCTKPDR KEFQKIAMAT AIGFAIMGFI GFFVKLIHIP INNIIVGG

UniProtKB: Protein transport protein Sec61 subunit gamma

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Macromolecule #3: Protein transport protein Sec61 subunit beta

MacromoleculeName: Protein transport protein Sec61 subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 2.486056 KDa
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)

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Macromolecule #4: Cyclic depsipeptide signal peptide mimic

MacromoleculeName: Cyclic depsipeptide signal peptide mimic / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.101966 KDa
SequenceString:
(JMO)(3EG)(MLE)(3EG)(JMX)L

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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
Component:
ConcentrationFormulaName
50.0 mMHEPSHEPES
300.0 mMNaClSodium chlorideSodium chloride
200.0 mMKoAcPotassium acetate
10.0 mMMgAcMagnesium acetate
1.0 mMDDTDithiothritol
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 0.2 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 283 K / Instrument: LEICA EM GP
DetailsPurified Ribosome-Sec61 complex

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.6 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 30294 / Average electron dose: 47.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1089031
Startup modelType of model: EMDB MAP
EMDB ID:

3245

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 136000
Details30294 movies
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

3jc2


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-7zl3:
Signal peptide mimicry primes Sec61 for client-selective inhibition

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