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.
Macromolecule #4: Cyclic depsipeptide signal peptide mimic
Macromolecule
Name: Cyclic depsipeptide signal peptide mimic / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)
Organism: synthetic construct (others)
Molecular weight
Theoretical: 1.101966 KDa
Sequence
String:
(JMO)(3EG)(MLE)(3EG)(JMX)L
-
Experimental details
-
Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
-
Sample preparation
Buffer
pH: 7.4 Component:
Concentration
Formula
Name
50.0 mM
HEPS
HEPES
300.0 mM
NaClSodium chloride
Sodium chloride
200.0 mM
KoAc
Potassium acetate
10.0 mM
MgAc
Magnesium acetate
1.0 mM
DDT
Dithiothritol
Grid
Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 0.2 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: AIR
Vitrification
Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 283 K / Instrument: LEICA EM GP
Details
Purified Ribosome-Sec61 complex
-
Electron microscopy
Microscope
FEI TITAN KRIOS
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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