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- PDB-9d6l: Human Sec61 complex inhibited by KZR-261 -

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Basic information

Entry
Database: PDB / ID: 9d6l
TitleHuman Sec61 complex inhibited by KZR-261
Components
  • Protein transport protein Sec61 subunit alpha isoform 1
  • Protein transport protein Sec61 subunit beta
  • Protein transport protein Sec61 subunit gamma
KeywordsMEMBRANE PROTEIN / Sec61 / translocon / translocation / endoplasmic reticulum / secretion
Function / homology
Function and homology information


endoplasmic reticulum Sec complex / pronephric nephron development / endoplasmic reticulum quality control compartment / cotranslational protein targeting to membrane / 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 / endoplasmic reticulum quality control compartment / cotranslational protein targeting to membrane / 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 / protein transmembrane transporter activity / SRP-dependent cotranslational protein targeting to membrane / response to type II interferon / ERAD pathway / guanyl-nucleotide exchange factor activity / calcium channel activity / ER-Phagosome pathway / ribosome binding / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsPark, E. / Wang, L.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_last ..._citation.journal_volume / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Protein transport protein Sec61 subunit gamma
C: Protein transport protein Sec61 subunit beta
A: Protein transport protein Sec61 subunit alpha isoform 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,7074
Polymers69,9423
Non-polymers7651
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Protein transport protein Sec61 subunit gamma


Mass: 7752.325 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SEC61G / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P60059
#2: Protein Protein transport protein Sec61 subunit beta


Mass: 9987.456 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SEC61B / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P60468
#3: Protein Protein transport protein Sec61 subunit alpha isoform 1 / Sec61 alpha-1


Mass: 52202.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Two cytosolic loops (amino acids residues 263-278 and 394-411) are mutated to enable Sec61 to bind to yeast Sec63
Source: (gene. exp.) Homo sapiens (human) / Gene: SEC61A1, SEC61A / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P61619
#4: Chemical ChemComp-A1A2B / 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


Mass: 765.057 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H61FN6O5S2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human-yeast chimeric Sec complex / Type: COMPLEX
Details: Contains human Sec61 complex, human-yeast chimeric Sec63, yeast Sec71, and yeast Sec72
Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.191 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Details: 25mM Tris-HCl pH 7.5, 100mM NaCl, 2mM DTT, 1mM EDTA, 0.04% beta-dodecylmaltoside, 0.008% cholesteryl hemisuccinate
SpecimenConc.: 7.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Warpparticle selection
2SerialEMimage acquisition
8PHENIXmodel refinement
10cryoSPARC4.5initial Euler assignment
11cryoSPARC4.5final Euler assignment
13cryoSPARC4.53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 351170 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0064316
ELECTRON MICROSCOPYf_angle_d0.755850
ELECTRON MICROSCOPYf_dihedral_angle_d11.132598
ELECTRON MICROSCOPYf_chiral_restr0.039690
ELECTRON MICROSCOPYf_plane_restr0.005708

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