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Yorodumi- PDB-7zl3: Signal peptide mimicry primes Sec61 for client-selective inhibition -
+Open data
-Basic information
Entry | Database: PDB / ID: 7zl3 | |||||||||
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Title | Signal peptide mimicry primes Sec61 for client-selective inhibition | |||||||||
Components |
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Keywords | MEMBRANE 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 | |||||||||
Biological species | Ovis aries (sheep) synthetic construct (others) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Rehan, S. / Paavilainen O, V. | |||||||||
Funding support | Finland, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7zl3.cif.gz | 100 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7zl3.ent.gz | 72.6 KB | Display | PDB format |
PDBx/mmJSON format | 7zl3.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7zl3_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 7zl3_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 7zl3_validation.xml.gz | 51.1 KB | Display | |
Data in CIF | 7zl3_validation.cif.gz | 72 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zl/7zl3 ftp://data.pdbj.org/pub/pdb/validation_reports/zl/7zl3 | HTTPS FTP |
-Related structure data
Related structure data | 14776MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 52034.062 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep) / References: UniProt: A0A6P3YN15 |
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#2: Protein | 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 | Mass: 2486.056 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep) |
#4: Protein/peptide | Mass: 1101.966 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component |
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Molecular weight | Value: 3.4 MDa / Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) | Organism: synthetic construct (others) | ||||||||||||||||||||||||||||||
Buffer solution | pH: 7.4 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Purified Ribosome-Sec61 complex | ||||||||||||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 283 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: OTHER / Nominal defocus max: 1200 nm / Nominal defocus min: 600 nm |
Image recording | Electron dose: 47 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 30294 |
-Processing
Software |
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Image processing | Details: 30294 movies | ||||||||||||||||||||||||
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 1089031 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 136000 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 3JC2 Accession code: 3JC2 / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||
Refine LS restraints |
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