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- EMDB-46598: Human-yeast chimeric Sec complex bound to KZR-261 inhibitor -

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Basic information

Entry
Database: EMDB / ID: EMD-46598
TitleHuman-yeast chimeric Sec complex bound to KZR-261 inhibitor
Map dataSharpened map
Sample
  • Complex: Human-yeast chimeric Sec complex
KeywordsSec61 / translocon / translocation / endoplasmic reticulum / secretion / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 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) releaseJun 25, 2025-
Map releaseJun 25, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46598.png

Downloads & links

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Map

FileDownload / File: emd_46598.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.46
Minimum - Maximum-8.370621 - 14.204388
Average (Standard dev.)0.009153856 (±0.23223644)
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_46598_msk_1.map
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Additional map: Averaged map

Fileemd_46598_additional_1.map
AnnotationAveraged map
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Half map: Half map 1

Fileemd_46598_half_map_1.map
AnnotationHalf map 1
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Half map: Half map 2

Fileemd_46598_half_map_2.map
AnnotationHalf map 2
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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

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Supramolecule #1: Human-yeast chimeric Sec complex

SupramoleculeName: Human-yeast chimeric Sec complex / type: complex / ID: 1 / Parent: 0
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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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 reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.0 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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