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- PDB-9fkd: Progesterone-bound DB3 Fab in complex with computationally design... -

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Basic information

Entry
Database: PDB / ID: 9fkd
TitleProgesterone-bound DB3 Fab in complex with computationally designed DBPro1156_2 protein binder
Components
  • (Anti-kappa Fab ...) x 2
  • DB3 Fab Heavy chain
  • DB3 Fab Light Chain
  • De novo designed DBPro1156_2 binder
KeywordsDE NOVO PROTEIN / progesterone / binder / de novo / Fab / anti-kappa
Function / homologyPROGESTERONE
Function and homology information
Biological speciessynthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsPacesa, M. / Marchand, A. / Correia, B.E.
Funding support Switzerland, 1items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2Jan 15, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_admin.last_update
Revision 1.3Jan 29, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.4Mar 26, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: De novo designed DBPro1156_2 binder
H: DB3 Fab Heavy chain
L: DB3 Fab Light Chain
K: Anti-kappa Fab Light Chain
I: Anti-kappa Fab Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,1276
Polymers107,8135
Non-polymers3141
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Antibody , 4 types, 4 molecules HLKI

#2: Antibody DB3 Fab Heavy chain


Mass: 25930.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Homo sapiens (human)
#3: Antibody DB3 Fab Light Chain


Mass: 24332.191 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Homo sapiens (human)
#4: Antibody Anti-kappa Fab Light Chain


Mass: 24115.680 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Homo sapiens (human)
#5: Antibody Anti-kappa Fab Heavy Chain


Mass: 25346.602 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Homo sapiens (human)

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Protein / Non-polymers , 2 types, 2 molecules B

#1: Protein De novo designed DBPro1156_2 binder


Mass: 8087.193 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#6: Chemical ChemComp-STR / PROGESTERONE


Mass: 314.462 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: hormone*YM

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Progesterone-bound DB3 Fab in complex with computationally designed DBPro1156_2 protein binder
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 0.10761566 MDa / Experimental value: NO
Source (natural)Organism: synthetic construct (others)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 3.9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: DB3 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
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 283.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Temperature (max): 192 K / Temperature (min): 186 K
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIXdev_5316model refinement
5cryoSPARCCTF correction
11cryoSPARC4.4.1final Euler assignment
13cryoSPARC4.4.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4048193
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 192055 / Num. of class averages: 1 / Symmetry type: POINT
RefinementCross valid method: NONE

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