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- EMDB-62274: CryoEM structure of Calcineurin-fusion Human endothelin receptor ... -

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Basic information

Entry
Database: EMDB / ID: EMD-62274
TitleCryoEM structure 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
        • Protein or peptide: Calcineurin-fusion endothelin receptor type-B
      • Complex: Calcineurin
    • Complex: FKBP16
      • Protein or peptide: Peptidyl-prolyl cis-trans isomerase FKBP1B
    • Complex: RES-701-3
      • Protein or peptide: RES-701-3
  • Ligand: CALCIUM ION
  • Ligand: FE (III) ION
  • Ligand: ZINC ION
  • Ligand: 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN
KeywordsGPCR / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / response to redox state / : / 'de novo' protein folding ...positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / response to redox state / : / 'de novo' protein folding / negative regulation of heart rate / FK506 binding / positive regulation of axon regeneration / channel regulator activity / smooth muscle contraction / response to vitamin E / calcium channel inhibitor activity / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / T cell proliferation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Ion homeostasis / release of sequestered calcium ion into cytosol / sarcoplasmic reticulum membrane / calcium channel complex / peptidyl-prolyl cis-trans isomerase activity / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / peptidylprolyl isomerase / calcium-mediated signaling / response to hydrogen peroxide / Stimuli-sensing channels / Z disc / positive regulation of cytosolic calcium ion concentration / protein refolding / transmembrane transporter binding / signaling receptor binding / membrane / cytoplasm
Similarity search - Function
: / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / Peptidyl-prolyl cis-trans isomerase domain superfamily
Similarity search - Domain/homology
Peptidyl-prolyl cis-trans isomerase FKBP1B
Similarity search - Component
Biological speciesHomo sapiens (human) / Streptomyces venezuelae (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsShihoya W / Akasaka H / 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_62274.png

Downloads & links

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Map

FileDownload / File: emd_62274.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
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

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.162 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.131
Minimum - Maximum-0.0017684082 - 2.0949502
Average (Standard dev.)0.0013585465 (±0.02585837)
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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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
        • Protein or peptide: Calcineurin-fusion endothelin receptor type-B
      • Complex: Calcineurin
    • Complex: FKBP16
      • Protein or peptide: Peptidyl-prolyl cis-trans isomerase FKBP1B
    • Complex: RES-701-3
      • Protein or peptide: RES-701-3
  • Ligand: CALCIUM ION
  • Ligand: FE (III) ION
  • Ligand: ZINC ION
  • Ligand: 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN

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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-#3
Source (natural)Organism: Homo sapiens (human)

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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: FKBP16

SupramoleculeName: FKBP16 / 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 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #6: Calcineurin

SupramoleculeName: Calcineurin / type: complex / ID: 6 / Parent: 2 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Calcineurin-fusion endothelin receptor type-B

MacromoleculeName: Calcineurin-fusion endothelin receptor type-B / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 102.498867 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: AMGQPVGAPG FPPDRATPLL QTAEIMTPPT KTLWPKGENL YFQGGGLAPA EVPKGDRTAG SPPRTISPPP CQGPIEIKET FKYINTVVS CLVFVLGIIG NSTLLYIIYK NKCMRNGPNI LIASLALGDL LHIVIAIPIN VYKLLAEDWP FGAEMCKLVP F IQKASVGI ...String:
AMGQPVGAPG FPPDRATPLL QTAEIMTPPT KTLWPKGENL YFQGGGLAPA EVPKGDRTAG SPPRTISPPP CQGPIEIKET FKYINTVVS CLVFVLGIIG NSTLLYIIYK NKCMRNGPNI LIASLALGDL LHIVIAIPIN VYKLLAEDWP FGAEMCKLVP F IQKASVGI TVLSLCALSI DRYRAVASWS RIKGIGVPKW TAVEIVLIWV VSVVLAVPEA IGFDIITMDY KGSYLRICLL HP VQKTAFM QFYATAKDWW LFSFYFCLPL AITAFFYTLM TCEMLRKKDA DEIKRLGKRF KKLDLDNSGS LSVEEFMSLP ELQ QNPLVQ RVIDIFDTDG NGEVDFKEFI EGVSQFSVKG DKEQKLRFAF RIYDMDKDGY ISNGELFQVL KMMVGNNLKD TQLQ QIVDK TIINADKDGD GRISFEEFCA VVGGLDIHKK MVVDVDHLKQ RREVAKTVFC LVLVFALCWL PLHLARILKL TLYNQ NDPN RCELLSFLLV LDYIGINMAS LNSCANPIAL YLVSKRFKNA FKSALCCWAQ SSGGGGSGGS SSGGVVKAVP FPPSHR LTA KEVFDNDGKP RVDILKAHLM KEGRLEETVA LRIITEGASI LRQEKNLLDI DAPVTVCGDI HGQFFDLMKL FEVGGSP AN TRYLFLGDYV DRGYFSIECV LYLWALKILY PKTLFLLRGN HECRHLTEYF TFKQECKIKY SERVYDACMD AFDCLPLA A LMNQQFLCVH GGLSPEINTL DDIRKLDRFK EPPAYGPMCD ILWSDPLEDF GNEKTQEHFT HNTVRGCSYF YSYPAVCEF LQHNNLLSIL RAHEAQDAGY RMYRKSQTTG FPSLITIFSA PNYLDVYNNK AAVLKYENNV MNIRQFNCSP HPYWLPNFMD VFTWSLPFV GEKVTEMLVN VLNLEVLFQ

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Macromolecule #2: Peptidyl-prolyl cis-trans isomerase FKBP1B

MacromoleculeName: Peptidyl-prolyl cis-trans isomerase FKBP1B / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: peptidylprolyl isomerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.771512 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGSGVEIETI SPGDGRTFPK KGQTCVVHYT GMLQNGKKFD SSRDRNKPFK FRIGKQEVIK GFEEGAAQMS LGQRAKLTCT PDVAYGATG HPGVIPPNAT LIFDVELLNL EHHHHHH

UniProtKB: Peptidyl-prolyl cis-trans isomerase FKBP1B

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Macromolecule #3: RES-701-3

MacromoleculeName: RES-701-3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Streptomyces venezuelae (bacteria)
Molecular weightTheoretical: 2.07818 KDa
Recombinant expressionOrganism: Streptomyces venezuelae (bacteria)
SequenceString:
GNWHGTSPDW FFNYYW

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Macromolecule #4: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #5: FE (III) ION

MacromoleculeName: FE (III) ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: FE
Molecular weightTheoretical: 55.845 Da

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Macromolecule #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #7: 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN

MacromoleculeName: 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN / type: ligand / ID: 7 / Number of copies: 1 / Formula: FK5
Molecular weightTheoretical: 804.018 Da
Chemical component information

ChemComp-FK5:
8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN / medication*YM

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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

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: 1.6 µm / Nominal defocus min: 0.8 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: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95937
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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