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- EMDB-52520: Pre-clinical characterization of novel multi-client inhibitors of... -

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Basic information

Entry
Database: EMDB / ID: EMD-52520
TitlePre-clinical characterization of novel multi-client inhibitors of Sec61 with broad anti-tumor activity
Map data
Sample
  • Complex: Sec61 translocon complex with small molecule
    • Protein or peptide: Protein transport protein Sec61 subunit alpha
    • Protein or peptide: Protein transport protein Sec61 subunit gamma
    • Protein or peptide: Protein transport protein Sec61 subunit beta
  • Ligand: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5-dimethylpiperazine-1-sulfonyl]-3-methyl-1,5,9-triazacyclododecane-1-sulfonyl}-N,N-dimethylaniline
KeywordsSec61 / ribosome / Protein translocation / PROTEIN TRANSPORT
Biological speciesOvis aries (sheep)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsShahid R / Paavilainen VO
Funding support Finland, 2 items
OrganizationGrant numberCountry
Academy of Finland338836 Finland
Jane and Aatos Erkko Foundation Finland
CitationJournal: J.Pharmacol.Exp.Ther. / Year: 2025
Title: Pre-clinical characterization of novel multi-client inhibitors of Sec61 with broad anti-tumor activity
Authors: Lowe E / Anderl JL / Bade D / Delgado-Martin C / Dong C / Fan RA / Fang Y / Jiang J / Johnson HW / Kempema A / McGilvray P / McMinn D / Millare B / Muchamuel T / Poweleit N / Qian Y / Rehan ...Authors: Lowe E / Anderl JL / Bade D / Delgado-Martin C / Dong C / Fan RA / Fang Y / Jiang J / Johnson HW / Kempema A / McGilvray P / McMinn D / Millare B / Muchamuel T / Poweleit N / Qian Y / Rehan S / Scapin G / Sugahara A / Tranter D / Tuch B / Wang J / Wang L / Whang JA / Zuno-Mitchell P / Paavilainen VO / Park E / Taunton J / Kirk CJ / Anand NK
History
DepositionJan 13, 2025-
Header (metadata) releaseJul 16, 2025-
Map releaseJul 16, 2025-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52520.png

Downloads & links

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Map

FileDownload / File: emd_52520.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 600 pix.
= 498. Å		0.83 Å/pix.
x 600 pix.
= 498. Å		0.83 Å/pix.
x 600 pix.
= 498. 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: 0.00001
Minimum - Maximum-0.39745665 - 1.2370273
Average (Standard dev.)0.0012252385 (±0.011247104)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 498.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_52520_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_52520_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 : Sec61 translocon complex with small molecule

EntireName: Sec61 translocon complex with small molecule
Components
  • Complex: Sec61 translocon complex with small molecule
    • Protein or peptide: Protein transport protein Sec61 subunit alpha
    • Protein or peptide: Protein transport protein Sec61 subunit gamma
    • Protein or peptide: Protein transport protein Sec61 subunit beta
  • Ligand: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5-dimethylpiperazine-1-sulfonyl]-3-methyl-1,5,9-triazacyclododecane-1-sulfonyl}-N,N-dimethylaniline

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Supramolecule #1: Sec61 translocon complex with small molecule

SupramoleculeName: Sec61 translocon complex with small molecule / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 3 MDa

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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: 45.829012 KDa
SequenceString: EIQKPERKIQ FKEKVLWTAI TLFIFLVCCQ IPLFGIMSSD SADPFYWMRV ILASNRGTLM ELGISPIVTS GLIMQLLAGA KKDRALFNG AQKLFGMIIT IGQSIVYVMT MGAGICLLIT IQLFVAGLIV LLLDELLQKG YGISLFIATN ICETIVWKAF S PTTVNTGR ...String:
EIQKPERKIQ FKEKVLWTAI TLFIFLVCCQ IPLFGIMSSD SADPFYWMRV ILASNRGTLM ELGISPIVTS GLIMQLLAGA KKDRALFNG AQKLFGMIIT IGQSIVYVMT MGAGICLLIT IQLFVAGLIV LLLDELLQKG YGISLFIATN ICETIVWKAF S PTTVNTGR GMEFEGAIIA LFHLLATRTD KVRALREAFY RQNLPNLMNL IATIFVFAVV IYFQGFRVDL PIKSARYRGQ YN TYPIKLF YTSNIPIILQ SALVSNLYVI SQMLSARFSG NLLVSLLGTW LCYYLSPPES FGSVLEDPVH AVVYIVFMLG SCA FFSKTW IEVSGSSAKD VAKQLKEQQM VMRGHRETSM VHELNRYIPT AAAFGGLCIG ALSVLADFLG AIGSGTGILL AVTI IYQYF EIFVKEQ

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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: 6.722062 KDa
SequenceString:
AAFVEPSRQF VKDSIRLVKR CTKPDRKEFQ KIAMATAIGF AIMGFIGFFV KLIHIPINN

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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: 2.316929 KDa
SequenceString:
VPVLVMSLLF IASVFMLHIW

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Macromolecule #4: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphen...

MacromoleculeName: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5-dimethylpiperazine-1-sulfonyl]-3-methyl-1,5,9-triazacyclododecane-1-sulfonyl}-N,N-dimethylaniline
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1A2B
Molecular weightTheoretical: 765.057 Da

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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

Concentration0.1 mg/mL
BufferpH: 7.4
GridMaterial: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 47.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1163355
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7zl3

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1564411
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-9hz5:
Pre-clinical characterization of novel multi-client inhibitors of Sec61 with broad anti-tumor activity

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