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- EMDB-46597: Human Sec61 complex inhibited by KZR-261 -

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Basic information

Entry
Database: EMDB / ID: EMD-46597
TitleHuman Sec61 complex inhibited by KZR-261
Map dataSharpened map
Sample
  • Complex: Human-yeast chimeric 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
  • 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 / translocon / translocation / endoplasmic reticulum / secretion / MEMBRANE PROTEIN
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 targeting to ER / protein insertion into ER membrane / post-translational protein targeting to endoplasmic reticulum membrane / SRP-dependent cotranslational 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 targeting to ER / protein insertion into ER membrane / post-translational protein targeting to endoplasmic reticulum membrane / SRP-dependent cotranslational protein targeting to membrane, translocation / signal sequence binding / SRP-dependent cotranslational protein targeting to membrane / post-translational protein targeting to membrane, translocation / endoplasmic reticulum organization / epidermal growth factor binding / retrograde protein transport, ER to cytosol / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / SRP-dependent cotranslational protein targeting to membrane / protein transmembrane transporter activity / response to type II interferon / ERAD pathway / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsPark E / Wang L
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J Pharmacol Exp Ther / Year: 2025
Title: Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity.
Authors: Eric Lowe / Janet L Anderl / David Bade / Cristina Delgado-Martin / Chengguo Dong / R Andrea Fan / Ying Fang / Jing Jiang / Henry W B Johnson / Aaron Kempema / Phil McGilvray / Dustin McMinn ...Authors: Eric Lowe / Janet L Anderl / David Bade / Cristina Delgado-Martin / Chengguo Dong / R Andrea Fan / Ying Fang / Jing Jiang / Henry W B Johnson / Aaron Kempema / Phil McGilvray / Dustin McMinn / Beatriz Millare / Tony Muchamuel / Nicole Poweleit / Yu Qian / Shahid Rehan / Giovanna Scapin / Ajia Sugahara / Dale Tranter / Brian Tuch / Jinhai Wang / Laurie Wang / Jennifer A Whang / Patricia Zuno-Mitchell / Ville O Paavilainen / Eunyong Park / Jack Taunton / Christopher J Kirk / Neel K Anand /
Abstract: The Sec61 translocon mediates entry of most secreted and transmembrane proteins into the endoplasmic reticulum, providing a novel therapeutic target to block the expression of protumorigenic factors. ...The Sec61 translocon mediates entry of most secreted and transmembrane proteins into the endoplasmic reticulum, providing a novel therapeutic target to block the expression of protumorigenic factors. Sec61 inhibitors with antitumor activity, mostly derived from natural products, have been reported. However, poor tolerability and suboptimal pharmaceutical properties have precluded their further development. We report here the discovery and characterization of KZR-834 and KZR-261, related small molecule analogs that directly bind to the Sec61 channel to potently inhibit the biogenesis of a subset of Sec61 client proteins. This client inhibition profile includes several tumorigenic factors, results in the activation of an endoplasmic reticulum stress response, and leads to broad anticancer effects in vitro. In vivo, KZR-261 was well tolerated and exhibits antitumor effects across multiple models, both as a single agent and in combination with anti-PD-1 immunotherapy. Based on the strength of this preclinical data, KZR-261 progressed into a phase I clinical trial (NCT05047536) in patients with malignant disease, where it was found to be well tolerated at doses that achieved durable stable disease. These results highlight the potential of Sec61 inhibition as a novel therapeutic target. SIGNIFICANCE STATEMENT: KZR-834 and KZR-261 are novel Sec61 inhibitors with the ability to block multiple Sec61 client proteins, leading to well-tolerated efficacy in in vivo cancer models. This represents a novel mechanism for blocking expression of oncogenic factors, including those not amenable to targeting through conventional methods.
History
DepositionAug 15, 2024-
Header (metadata) releaseJul 23, 2025-
Map releaseJul 23, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46597.png

Downloads & links

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Map

FileDownload / File: emd_46597.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 256 pix.
= 294.4 Å		1.15 Å/pix.
x 256 pix.
= 294.4 Å		1.15 Å/pix.
x 256 pix.
= 294.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.46
Minimum - Maximum-6.7435865 - 11.693960000000001
Average (Standard dev.)0.009175664 (±0.18624692)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 294.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_46597_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Averaged map

Fileemd_46597_additional_1.map
AnnotationAveraged map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map1

Fileemd_46597_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_46597_half_map_2.map
AnnotationHalf map2
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human-yeast chimeric Sec complex

EntireName: Human-yeast chimeric Sec complex
Components
  • Complex: Human-yeast chimeric 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
  • 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: Human-yeast chimeric Sec complex

SupramoleculeName: Human-yeast chimeric Sec complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: Contains human Sec61 complex, human-yeast chimeric Sec63, yeast Sec71, and yeast Sec72
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 191 KDa

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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 (amino acids residues 263-278 and 394-411) are mutated to enable Sec61 to bind to yeast Sec63
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: 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

Concentration7.3 mg/mL
BufferpH: 7.5
Details: 25mM Tris-HCl pH 7.5, 100mM NaCl, 2mM DTT, 1mM EDTA, 0.04% beta-dodecylmaltoside, 0.008% cholesteryl hemisuccinate
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (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
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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.5) / Number images used: 351170
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: cryoSPARC (ver. 4.5)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5)
FSC plot (resolution estimation)

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