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- EMDB-73558: Human Sec61 complex bound to coibamide A -

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Basic information

Entry
Database: EMDB / ID: EMD-73558
TitleHuman Sec61 complex bound to coibamide A
Map dataSharpened map
Sample
  • Complex: Chimeric (human-yeast) Sec complex bound to coibamide A
    • Complex: Chimeric (human-yeast) Sec complex
      • 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
    • Complex: coibamide A
      • Protein or peptide: Coibamide A
  • Ligand: CHOLESTEROL
KeywordsSec61 / Coibamide / Endoplasmic reticulum / depsipeptide / PROTEIN TRANSPORT
Function / homology
Function and homology information


endoplasmic reticulum Sec complex / pronephric nephron development / cotranslational protein targeting to membrane / endoplasmic reticulum quality control compartment / Ssh1 translocon complex / Sec61 translocon complex / protein insertion into ER membrane / post-translational protein targeting to endoplasmic reticulum membrane / protein targeting to ER / post-translational protein targeting to membrane, translocation ...endoplasmic reticulum Sec complex / pronephric nephron development / cotranslational protein targeting to membrane / endoplasmic reticulum quality control compartment / Ssh1 translocon complex / Sec61 translocon complex / protein insertion into ER membrane / post-translational protein targeting to endoplasmic reticulum membrane / protein targeting to ER / post-translational protein targeting to membrane, translocation / SRP-dependent cotranslational protein targeting to membrane, translocation / endoplasmic reticulum organization / SRP-dependent cotranslational protein targeting to membrane / signal sequence receptor activity / epidermal growth factor binding / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / retrograde protein transport, ER to cytosol / transmembrane protein transporter activity / SRP-dependent cotranslational protein targeting to membrane / ERAD pathway / response to type II interferon / guanyl-nucleotide exchange factor activity / calcium channel activity / ribosome binding / ER-Phagosome pathway / endoplasmic reticulum membrane / endoplasmic reticulum / RNA binding / membrane / cytosol
Similarity search - Function
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 / Protein secE/sec61-gamma signature. / Protein secY signature 1. / Protein secY signature 2. ...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 / 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
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) / Leptolyngbya sp. (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsPark E / Wang L
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Cell Chem Biol / Year: 2026
Title: Structure-based design of Sec61 translocon targeting prodrugs minimize off-target toxicity.
Authors: Qingqing Hao / Laurie Wang / Hui Pan / Xihui Xiao / Wenyan Dong / Wencong Pan / Jingjing Sun / Wu Su / Lijing Fang / Eunyong Park / Guiyang Yao /
Abstract: Coibamide A (CbA) is a cyclic depsipeptide that inhibits the function of the Sec61 translocon and exhibits significant antitumor activity. However, its broad Sec61 inhibition results in non-selective ...Coibamide A (CbA) is a cyclic depsipeptide that inhibits the function of the Sec61 translocon and exhibits significant antitumor activity. However, its broad Sec61 inhibition results in non-selective cytotoxicity, limiting therapeutic applications. To elucidate the molecular mechanism of CbA-mediated Sec61 blockade and enable rational prodrug design, we determined the cryo-EM structure of human Sec61 bound to CbA at 3.1 Å resolution. The structure reveals that CbA adopts a distinctive lasso-like conformation and occupies the lateral gate of Sec61, a binding site shared with other Sec61 inhibitors, while forming a particularly more expansive set of interactions with the lateral gate. Guided by these structural insights, we conducted structure-activity relationship studies and developed prodrug strategies that modulate CbA's antitumor activity through the controlled perturbation of intramolecular and protein hydrogen bonding interactions. Together, these results establish a structure-guided strategy for prodrug design of CbA and demonstrate the general applicability of backbone-caging to enhance the tolerability of Sec61 inhibitors.
History
DepositionOct 25, 2025-
Header (metadata) releaseJul 22, 2026-
Map releaseJul 22, 2026-
UpdateJul 22, 2026-
Current statusJul 22, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73558.png

Downloads & links

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Map

FileReleased
AnnotationSharpened map
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: 1.4
Minimum - Maximum-4.7655635 - 7.85606
Average (Standard dev.)0.024909047 (±0.15790322)
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: Unsharpened map

Fileemd_73558_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map1

Fileemd_73558_half_map_1.map
AnnotationHalf map1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map2

Fileemd_73558_half_map_2.map
AnnotationHalf map2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Chimeric (human-yeast) Sec complex bound to coibamide A

EntireName: Chimeric (human-yeast) Sec complex bound to coibamide A
Components
  • Complex: Chimeric (human-yeast) Sec complex bound to coibamide A
    • Complex: Chimeric (human-yeast) Sec complex
      • 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
    • Complex: coibamide A
      • Protein or peptide: Coibamide A
  • Ligand: CHOLESTEROL

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Supramolecule #1: Chimeric (human-yeast) Sec complex bound to coibamide A

SupramoleculeName: Chimeric (human-yeast) Sec complex bound to coibamide A
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: Chimeric (human-yeast) Sec complex

SupramoleculeName: Chimeric (human-yeast) Sec complex / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: coibamide A

SupramoleculeName: coibamide A / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Leptolyngbya sp. (bacteria) / Synthetically produced: Yes

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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 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.752325 KDa
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 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.987456 KDa
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
Details: Two cytosolic loops (263-278 and 394-411) are replaced with the homologous segments of the yeast (S. cerevisiae) Sec61 protein.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.202438 KDa
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: Coibamide A

MacromoleculeName: Coibamide A / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Leptolyngbya sp. (bacteria)
Molecular weightTheoretical: 1.305642 KDa
SequenceString:
(O7G)(VAD)(A1CZ7)(MLE)(NZC)(A1CZ7)(IML)A(MLE)(0A1) (33X)

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average exposure time: 6.8 sec. / 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: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.7) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ab initio reconstruction by CryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7) / Number images used: 284979
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: cryoSPARC (ver. 4.7)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7)
FSC plot (resolution estimation)

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