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- EMDB-62273: focused on refinement endothelin receptor type-B of Calcineurin-f... -

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Basic information

Entry
Database: EMDB / ID: EMD-62273
Titlefocused on refinement endothelin receptor type-B of Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
Map data
Sample
  • Complex: Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
    • Complex: Calcineurin-fusion endothelin receptor type-B
      • Complex: Endothelin receptor type-B
      • Complex: Calcineurin
    • Complex: FKBP12
    • Complex: RES-701-3
KeywordsGPCR / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human) / Streptomyces venezuelae (bacteria) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsAkasaka H / Shihoya W / Nureki O
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21H05037 Japan
CitationJournal: Nat Commun / Year: 2025
Title: Structure of a lasso peptide bound ET receptor provides insights into the mechanism of GPCR inverse agonism.
Authors: Wataru Shihoya / Hiroaki Akasaka / Peter A Jordan / Anna Lechner / Bethany K Okada / Gabriella Costa Machado da Cruz / Fumiya K Sano / Tatsuki Tanaka / Ryo Kawahara / Rajan Chaudhari / ...Authors: Wataru Shihoya / Hiroaki Akasaka / Peter A Jordan / Anna Lechner / Bethany K Okada / Gabriella Costa Machado da Cruz / Fumiya K Sano / Tatsuki Tanaka / Ryo Kawahara / Rajan Chaudhari / Hiroko Masamune / Mark J Burk / Osamu Nureki /
Abstract: Lasso peptides exhibit a unique lariat-like knotted structure imparting exceptional stability and thus show promise as therapeutic agents that target cell-surface receptors. One such receptor is the ...Lasso peptides exhibit a unique lariat-like knotted structure imparting exceptional stability and thus show promise as therapeutic agents that target cell-surface receptors. One such receptor is the human endothelin type B receptor (ET), which is implicated in challenging cancers with poor immunotherapy responsiveness. The Streptomyces-derived lasso peptide, RES-701-3, is a selective inhibitor for ET and a compelling candidate for therapeutic development. However, meager production from a genetically recalcitrant host has limited further structure-activity relationship studies of this potent inhibitor. Here, we report cryo-electron microscopy structures of ET receptor in both its apo form and complex with RES-701-3, facilitated by a calcineurin-fusion strategy. Hydrophobic interactions between RES-701-3 and the transmembrane region of the receptor, especially involving two tryptophan residues, play a crucial role in RES-701-3 binding. Furthermore, RES-701-3 prevents conformational changes associated with G-protein coupling, explaining its inverse agonist activity. A comparative analysis with other lasso peptides and their target proteins highlights the potential of lasso peptides as precise drug candidates for G-protein-coupled receptors. This structural insight into RES-701-3 binding to ET receptor offers valuable information for the development of novel therapeutics targeting this receptor and provides a broader understanding of lasso peptide interactions with human cell-surface receptors.
History
DepositionNov 3, 2024-
Header (metadata) releaseMay 7, 2025-
Map releaseMay 7, 2025-
UpdateMay 7, 2025-
Current statusMay 7, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62273.png

Downloads & links

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Map

FileDownload / File: emd_62273.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 200 pix.
= 232.4 Å		1.16 Å/pix.
x 200 pix.
= 232.4 Å		1.16 Å/pix.
x 200 pix.
= 232.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.162 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.45
Minimum - Maximum-0.91611624 - 1.7447387
Average (Standard dev.)-0.002051458 (±0.04175604)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 232.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_62273_msk_1.map
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Half map: #1

Fileemd_62273_half_map_1.map
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Half map: #2

Fileemd_62273_half_map_2.map
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Sample components

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Entire : Calcineurin-fusion Human endothelin receptor type-B in complex wi...

EntireName: Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
Components
  • Complex: Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
    • Complex: Calcineurin-fusion endothelin receptor type-B
      • Complex: Endothelin receptor type-B
      • Complex: Calcineurin
    • Complex: FKBP12
    • Complex: RES-701-3

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Supramolecule #1: Calcineurin-fusion Human endothelin receptor type-B in complex wi...

SupramoleculeName: Calcineurin-fusion Human endothelin receptor type-B in complex with RES-701-3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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Supramolecule #2: Calcineurin-fusion endothelin receptor type-B

SupramoleculeName: Calcineurin-fusion endothelin receptor type-B / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: FKBP12

SupramoleculeName: FKBP12 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: RES-701-3

SupramoleculeName: RES-701-3 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Streptomyces venezuelae (bacteria)

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Supramolecule #5: Endothelin receptor type-B

SupramoleculeName: Endothelin receptor type-B / type: complex / ID: 5 / Parent: 2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #6: Calcineurin

SupramoleculeName: Calcineurin / type: complex / ID: 6 / Parent: 2
Source (natural)Organism: Mus musculus (house mouse)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration7 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7dh5

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95937
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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