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- EMDB-50522: Progesterone-bound DB3 Fab in complex with computationally design... -

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Basic information

Entry
Database: EMDB / ID: EMD-50522
TitleProgesterone-bound DB3 Fab in complex with computationally designed DBPro1156_2 protein binder
Map data
Sample
  • Complex: Progesterone-bound DB3 Fab in complex with computationally designed DBPro1156_2 protein binder
    • Protein or peptide: De novo designed DBPro1156_2 binder
    • Protein or peptide: DB3 Fab Heavy chain
    • Protein or peptide: DB3 Fab Light Chain
    • Protein or peptide: Anti-kappa Fab Light Chain
    • Protein or peptide: Anti-kappa Fab Heavy Chain
  • Ligand: PROGESTERONE
Keywordsprogesterone / binder / de novo / Fab / anti-kappa / DE NOVO PROTEIN
Biological speciessynthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsPacesa M / Marchand A / Correia BE
Funding support Switzerland, 1 items
OrganizationGrant numberCountry
Swiss National Science Foundation310030_197724 Switzerland
CitationJournal: Nature / Year: 2025
Title: Targeting protein-ligand neosurfaces with a generalizable deep learning tool.
Authors: Anthony Marchand / Stephen Buckley / Arne Schneuing / Martin Pacesa / Maddalena Elia / Pablo Gainza / Evgenia Elizarova / Rebecca M Neeser / Pao-Wan Lee / Luc Reymond / Yangyang Miao / Leo ...Authors: Anthony Marchand / Stephen Buckley / Arne Schneuing / Martin Pacesa / Maddalena Elia / Pablo Gainza / Evgenia Elizarova / Rebecca M Neeser / Pao-Wan Lee / Luc Reymond / Yangyang Miao / Leo Scheller / Sandrine Georgeon / Joseph Schmidt / Philippe Schwaller / Sebastian J Maerkl / Michael Bronstein / Bruno E Correia /
Abstract: Molecular recognition events between proteins drive biological processes in living systems. However, higher levels of mechanistic regulation have emerged, in which protein-protein interactions are ...Molecular recognition events between proteins drive biological processes in living systems. However, higher levels of mechanistic regulation have emerged, in which protein-protein interactions are conditioned to small molecules. Despite recent advances, computational tools for the design of new chemically induced protein interactions have remained a challenging task for the field. Here we present a computational strategy for the design of proteins that target neosurfaces, that is, surfaces arising from protein-ligand complexes. To develop this strategy, we leveraged a geometric deep learning approach based on learned molecular surface representations and experimentally validated binders against three drug-bound protein complexes: Bcl2-venetoclax, DB3-progesterone and PDF1-actinonin. All binders demonstrated high affinities and accurate specificities, as assessed by mutational and structural characterization. Remarkably, surface fingerprints previously trained only on proteins could be applied to neosurfaces induced by interactions with small molecules, providing a powerful demonstration of generalizability that is uncommon in other deep learning approaches. We anticipate that such designed chemically induced protein interactions will have the potential to expand the sensing repertoire and the assembly of new synthetic pathways in engineered cells for innovative drug-controlled cell-based therapies.
History
DepositionJun 3, 2024-
Header (metadata) releaseOct 30, 2024-
Map releaseOct 30, 2024-
UpdateMar 26, 2025-
Current statusMar 26, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50522.png

Downloads & links

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Map

FileDownload / File: emd_50522.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 360 pix.
= 236.88 Å		0.66 Å/pix.
x 360 pix.
= 236.88 Å		0.66 Å/pix.
x 360 pix.
= 236.88 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.658 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.061374247 - 0.113680385
Average (Standard dev.)0.000015626187 (±0.0024258366)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 236.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50522_msk_1.map
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Half map: #1

Fileemd_50522_half_map_1.map
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Histogram

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Half map: #2

Fileemd_50522_half_map_2.map
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Sample components

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Entire : Progesterone-bound DB3 Fab in complex with computationally design...

EntireName: Progesterone-bound DB3 Fab in complex with computationally designed DBPro1156_2 protein binder
Components
  • Complex: Progesterone-bound DB3 Fab in complex with computationally designed DBPro1156_2 protein binder
    • Protein or peptide: De novo designed DBPro1156_2 binder
    • Protein or peptide: DB3 Fab Heavy chain
    • Protein or peptide: DB3 Fab Light Chain
    • Protein or peptide: Anti-kappa Fab Light Chain
    • Protein or peptide: Anti-kappa Fab Heavy Chain
  • Ligand: PROGESTERONE

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Supramolecule #1: Progesterone-bound DB3 Fab in complex with computationally design...

SupramoleculeName: Progesterone-bound DB3 Fab in complex with computationally designed DBPro1156_2 protein binder
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 107.61566 KDa

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Macromolecule #1: De novo designed DBPro1156_2 binder

MacromoleculeName: De novo designed DBPro1156_2 binder / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 8.087193 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
DEKAKTAETL IWQLFGKAMQ QSDPNEAEKL LKKAEELAKK ANDPRLEQVV RQHQVVVRFL VGGSHHHHHH

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Macromolecule #2: DB3 Fab Heavy chain

MacromoleculeName: DB3 Fab Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 25.93093 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ETGQIQLVQS GPELKKPGET VKISCKASGY AFTNYGVNWV KEAPGKELKW MGWINIYTGE PTYVDDFKGR FAFSLETSAS TAYLEINNL KNEDTATYFC TRGDYVNWYF DVWGAGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
ETGQIQLVQS GPELKKPGET VKISCKASGY AFTNYGVNWV KEAPGKELKW MGWINIYTGE PTYVDDFKGR FAFSLETSAS TAYLEINNL KNEDTATYFC TRGDYVNWYF DVWGAGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTGTKHHHHH H

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Macromolecule #3: DB3 Fab Light Chain

MacromoleculeName: DB3 Fab Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 24.332191 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ETGDVVMTQI PLSLPVSLGE QASISCRSSQ SLIHSNGNTY LHWYLQKPGQ SPKLLMYKVS NRFYGVPDRF SGSGSGTDFT LKISRVEAE DLGIYFCSQS SHVPPTFGGG TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD N ALQSGNSQ ...String:
ETGDVVMTQI PLSLPVSLGE QASISCRSSQ SLIHSNGNTY LHWYLQKPGQ SPKLLMYKVS NRFYGVPDRF SGSGSGTDFT LKISRVEAE DLGIYFCSQS SHVPPTFGGG TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD N ALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC

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Macromolecule #4: Anti-kappa Fab Light Chain

MacromoleculeName: Anti-kappa Fab Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 24.11568 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ETGSIVMTQT PKFLFVSAGD RVTITCKASQ SVSNDVEWYQ QKPGQSPKLM IYFASKRYNG VPDRFTGSGF GTEFTFTIST VQAEDLAVY FCQQDYSSPW TFGGGTKLEI KRADAAPTVS IFPPSSEQLT SGGASVVCFL NNFYPKDINV KWKIDGSERQ N GVLNSWTD ...String:
ETGSIVMTQT PKFLFVSAGD RVTITCKASQ SVSNDVEWYQ QKPGQSPKLM IYFASKRYNG VPDRFTGSGF GTEFTFTIST VQAEDLAVY FCQQDYSSPW TFGGGTKLEI KRADAAPTVS IFPPSSEQLT SGGASVVCFL NNFYPKDINV KWKIDGSERQ N GVLNSWTD QDSKDSTYSM SSTLTLTKDE YERHNSYTCE ATHKTSTSPI VKSFNRGEC

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Macromolecule #5: Anti-kappa Fab Heavy Chain

MacromoleculeName: Anti-kappa Fab Heavy Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 25.346602 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ETGEVKLLES GGGLVQPGRS LRLSCIASGF DFSGYWMTWV RQAPGKGLEW IGDINPDSST INSTPSLKDK VIISRDNAKN TLFLQMSKV RSEDTALYYC AQRGNYVPFP YWGQGTLVTV SAAKTTPPSV YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT V TWNSGSLS ...String:
ETGEVKLLES GGGLVQPGRS LRLSCIASGF DFSGYWMTWV RQAPGKGLEW IGDINPDSST INSTPSLKDK VIISRDNAKN TLFLQMSKV RSEDTALYYC AQRGNYVPFP YWGQGTLVTV SAAKTTPPSV YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT V TWNSGSLS SGVHTFPAVL QSDLYTLSSS VTVPSSTWPS ETVTCNVAHP ASSTKVDKKI VPRDCGCKGT KHHHHHH

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Macromolecule #6: PROGESTERONE

MacromoleculeName: PROGESTERONE / type: ligand / ID: 6 / Number of copies: 1 / Formula: STR
Molecular weightTheoretical: 314.462 Da
Chemical component information

ChemComp-STR:
PROGESTERONE / hormone*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

Concentration3.9 mg/mL
BufferpH: 7.5
GridModel: Quantifoil / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 283.15 K / Instrument: FEI VITROBOT MARK IV
DetailsDB3 Fab and anti-Kappa Fab were pre-purified on SEC, while DBPro1156_2 de novo binder was added in 3-fold excess before grid freezing

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Electron microscopy

MicroscopeTFS KRIOS
TemperatureMin: 186.0 K / Max: 192.0 K
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4048193
Startup modelType of model: INSILICO MODEL
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 192055
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.1)
FSC plot (resolution estimation)

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