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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 / 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)
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: Pre-clinical characterization of novel multi-client inhibitors of Sec61 with broad anti-tumor activity
Authors: Lowe, E. / Anderl, J.L. / Bade, D. / Delgado-Martin, C. / Dong, C. / Fan, R.A. / Fang, Y. / Jiang, J. / Johnson, H.W. / Kempema, A. / McGilvray, P. / McMinn, D. / Millare, B. / Muchamuel, T. ...Authors: Lowe, E. / Anderl, J.L. / Bade, D. / Delgado-Martin, C. / Dong, C. / Fan, R.A. / Fang, Y. / Jiang, J. / Johnson, H.W. / 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, J.A. / Zuno-Mitchell, P. / Paavilainen, V.O. / Park, E. / Taunton, J. / Kirk, C.J. / Anand, N.K.
History
DepositionAug 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release

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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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