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- PDB-8s1x: Crystal structure of Actinonin-bound PDF1 and the computationally... -

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Basic information

Entry
Database: PDB / ID: 8s1x
TitleCrystal structure of Actinonin-bound PDF1 and the computationally designed DBAct553_1 protein binder
Components
  • DBAct553_1
  • Peptide deformylase
KeywordsDE NOVO PROTEIN / Actinonin / de novo / computational / binder / CID / switch / deformylase
Function / homology
Function and homology information


peptide deformylase / peptide deformylase activity / co-translational protein modification / translation / metal ion binding
Similarity search - Function
Peptide deformylase / Peptide deformylase superfamily / Polypeptide deformylase
Similarity search - Domain/homology
ACTINONIN / FORMIC ACID / : / PHOSPHATE ION / Peptide deformylase
Similarity search - Component
Biological speciesPseudomonas aeruginosa (bacteria)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsMarchand, A. / Pacesa, M. / Correia, B.E.
Funding supportEuropean Union, Switzerland, 2items
OrganizationGrant numberCountry
European Research Council (ERC)716058European Union
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
DepositionFeb 16, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2025Group: Database references / Category: citation
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
Revision 1.2Jan 29, 2025Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Mar 26, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Peptide deformylase
B: DBAct553_1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,78217
Polymers27,5442
Non-polymers1,23815
Water1,36976
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4730 Å2
ΔGint-67 kcal/mol
Surface area11590 Å2
Unit cell
Length a, b, c (Å)49.440, 75.010, 83.160
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Peptide deformylase / PDF / Polypeptide deformylase


Mass: 19391.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Actionin / Source: (gene. exp.) Pseudomonas aeruginosa (bacteria) / Gene: def, PA0019 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9I7A8, peptide deformylase
#2: Protein DBAct553_1


Mass: 8152.354 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Actionin / Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Non-polymers , 6 types, 91 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-BB2 / ACTINONIN / 2-[(FORMYL-HYDROXY-AMINO)-METHYL]-HEPTANOIC ACID [1-(2-HYDROXYMETHYL-PYRROLIDINE-1-CARBONYL)-2-METHYL-PROPYL]-AMIDE


Mass: 385.498 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H35N3O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: antitumor, antibiotic*YM
#5: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: CH2O2
#6: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.8 Å3/Da / Density % sol: 56.06 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 6.2
Details: 0.2 M Sodium Formate, 0.1 M Sodium Phosphate pH 6.2, 20% (v/v) PEG smear, 10% (v/v) glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.87313 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Feb 11, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.87313 Å / Relative weight: 1
ReflectionResolution: 1.88→55.7 Å / Num. obs: 24990 / % possible obs: 96.9 % / Redundancy: 4.3 % / Biso Wilson estimate: 44.77 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.044 / Net I/σ(I): 15
Reflection shellResolution: 1.88→1.91 Å / Redundancy: 4.4 % / Rmerge(I) obs: 1.125 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1266 / CC1/2: 0.426 / % possible all: 99.6

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Processing

Software
NameVersionClassification
PHENIX1.21_5184refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→55.7 Å / SU ML: 0.2366 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.4881
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2027 1255 5.02 %
Rwork0.1837 23727 -
obs0.1846 24982 96.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.21 Å2
Refinement stepCycle: LAST / Resolution: 1.88→55.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1842 0 73 76 1991
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00641939
X-RAY DIFFRACTIONf_angle_d0.77912604
X-RAY DIFFRACTIONf_chiral_restr0.0509289
X-RAY DIFFRACTIONf_plane_restr0.0093339
X-RAY DIFFRACTIONf_dihedral_angle_d15.6309777
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.88-1.960.34161490.30372652X-RAY DIFFRACTION99.26
1.96-2.050.28121330.27722642X-RAY DIFFRACTION98.44
2.05-2.150.27731450.23192647X-RAY DIFFRACTION98.52
2.15-2.290.24351470.19792598X-RAY DIFFRACTION97.9
2.29-2.460.18661460.19062638X-RAY DIFFRACTION98.1
2.46-2.710.23931340.19612646X-RAY DIFFRACTION97.17
2.71-3.110.20451390.18962626X-RAY DIFFRACTION95.84
3.11-3.910.17751510.17232557X-RAY DIFFRACTION93.7
3.91-55.70.18741110.16752721X-RAY DIFFRACTION92.97

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