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- PDB-7zl3: Signal peptide mimicry primes Sec61 for client-selective inhibition -

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Basic information

Entry
Database: PDB / ID: 7zl3
TitleSignal peptide mimicry primes Sec61 for client-selective inhibition
Components
  • Cyclic depsipeptide signal peptide mimic
  • Protein transport protein Sec61 subunit alphaProtein targeting
  • Protein transport protein Sec61 subunit betaProtein targeting
  • Protein transport protein Sec61 subunit gammaProtein targeting
KeywordsMEMBRANE PROTEIN / Sec61 Translocon / cryoEM / Protein biogenesis
Function / homology
Function and homology information


protein transmembrane transporter activity / protein targeting / protein transport / endoplasmic reticulum membrane
Similarity search - Function
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 ...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
Translocon Sec61/SecY plug domain-containing protein / Protein transport protein Sec61 subunit gamma
Similarity search - Component
Biological speciesOvis aries (sheep)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsRehan, S. / Paavilainen O, V.
Funding support Finland, 1items
OrganizationGrant numberCountry
Academy of Finland314672 Finland
CitationJournal: Nat Chem Biol / Year: 2023
Title: Signal peptide mimicry primes Sec61 for client-selective inhibition.
Authors: Shahid Rehan / Dale Tranter / Phillip P Sharp / Gregory B Craven / Eric Lowe / Janet L Anderl / Tony Muchamuel / Vahid Abrishami / Suvi Kuivanen / Nicole A Wenzell / Andy Jennings / ...Authors: Shahid Rehan / Dale Tranter / Phillip P Sharp / Gregory B Craven / Eric Lowe / Janet L Anderl / Tony Muchamuel / Vahid Abrishami / Suvi Kuivanen / Nicole A Wenzell / Andy Jennings / Chakrapani Kalyanaraman / Tomas Strandin / Matti Javanainen / Olli Vapalahti / Matthew P Jacobson / Dustin McMinn / Christopher J Kirk / Juha T Huiskonen / Jack Taunton / Ville O Paavilainen /
Abstract: Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. ...Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein biogenesis factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets the Sec61 translocon and selectively disrupts secretory and membrane protein biogenesis in a signal peptide-dependent manner. KZR-8445 potently inhibits the secretion of pro-inflammatory cytokines in primary immune cells and is highly efficacious in a mouse model of rheumatoid arthritis. A cryogenic electron microscopy structure reveals that KZR-8445 occupies the fully opened Se61 lateral gate and blocks access to the lumenal plug domain. KZR-8445 binding stabilizes the lateral gate helices in a manner that traps select signal peptides in the Sec61 channel and prevents their movement into the lipid bilayer. Our results establish a framework for the structure-guided discovery of novel therapeutics that selectively modulate Sec61-mediated protein biogenesis.
History
DepositionApr 13, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 6, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Refinement description
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / em_3d_fitting_list / pdbx_validate_main_chain_plane / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / pdbx_validate_rmsd_bond / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _struct_conn.ptnr1_label_atom_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein transport protein Sec61 subunit alpha
B: Protein transport protein Sec61 subunit gamma
C: Protein transport protein Sec61 subunit beta
E: Cyclic depsipeptide signal peptide mimic


Theoretical massNumber of molelcules
Total (without water)63,3744
Polymers63,3744
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Protein transport protein Sec61 subunit alpha / Protein targeting


Mass: 52034.062 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep) / References: UniProt: A0A6P3YN15
#2: Protein Protein transport protein Sec61 subunit gamma / Protein targeting


Mass: 7752.325 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep) / References: UniProt: W5PP18
#3: Protein/peptide Protein transport protein Sec61 subunit beta / Protein targeting


Mass: 2486.056 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep)
#4: Protein/peptide Cyclic depsipeptide signal peptide mimic


Mass: 1101.966 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSource
1Protein conducting Sec61 translocon complexCOMPLEX#1-#2, #40NATURAL
2Protein conducting Sec61 translocon complexCOMPLEX#1-#21NATURAL
3Signal peptide mimicCOMPLEX#41RECOMBINANT
Molecular weightValue: 3.4 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Ovis aries (sheep)9940
33synthetic construct (others)32630
Source (recombinant)Organism: synthetic construct (others)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMHEPESHEPS1
2300 mMSodium chlorideNaClSodium chloride1
3200 mMPotassium acetateKoAc1
410 mMMagnesium acetateMgAc1
51 mMDithiothritolDDT1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Purified Ribosome-Sec61 complex
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 283 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: OTHER / Nominal defocus max: 1200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 47 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 30294

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Processing

Software
NameVersionClassificationNB
PHENIX1.19.2_4158:refinement
UCSF ChimeraX1.3/v9model building
Image processingDetails: 30294 movies
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1089031
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 136000 / Symmetry type: POINT
Atomic model buildingPDB-ID: 3JC2

3jc2


Accession code: 3JC2 / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043771
ELECTRON MICROSCOPYf_angle_d0.6525111
ELECTRON MICROSCOPYf_dihedral_angle_d6.739509
ELECTRON MICROSCOPYf_chiral_restr0.042603
ELECTRON MICROSCOPYf_plane_restr0.004625

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