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- PDB-7xad: Crystal strucutre of PD-L1 and DBL2_02 designed protein binder -

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Basic information

Entry
Database: PDB / ID: 7xad
TitleCrystal strucutre of PD-L1 and DBL2_02 designed protein binder
Components
  • DBL2_02 binder
  • Programmed cell death 1 ligand 1
KeywordsIMMUNE SYSTEM / PD-L1
Function / homology
Function and homology information


positive regulation of tolerance induction to tumor cell / negative regulation of tumor necrosis factor superfamily cytokine production / positive regulation of activated CD8-positive, alpha-beta T cell apoptotic process / negative regulation of CD8-positive, alpha-beta T cell activation / TRIF-dependent toll-like receptor signaling pathway / negative regulation of CD4-positive, alpha-beta T cell proliferation / STAT3 nuclear events downstream of ALK signaling / negative regulation of interleukin-10 production / negative regulation of activated T cell proliferation / positive regulation of interleukin-10 production ...positive regulation of tolerance induction to tumor cell / negative regulation of tumor necrosis factor superfamily cytokine production / positive regulation of activated CD8-positive, alpha-beta T cell apoptotic process / negative regulation of CD8-positive, alpha-beta T cell activation / TRIF-dependent toll-like receptor signaling pathway / negative regulation of CD4-positive, alpha-beta T cell proliferation / STAT3 nuclear events downstream of ALK signaling / negative regulation of interleukin-10 production / negative regulation of activated T cell proliferation / positive regulation of interleukin-10 production / negative regulation of type II interferon production / PD-1 signaling / positive regulation of T cell proliferation / T cell costimulation / response to cytokine / recycling endosome membrane / actin cytoskeleton / early endosome membrane / cellular response to lipopolysaccharide / adaptive immune response / transcription coactivator activity / cell surface receptor signaling pathway / positive regulation of cell migration / immune response / external side of plasma membrane / signal transduction / extracellular exosome / nucleoplasm / plasma membrane
Similarity search - Function
CD80-like, immunoglobulin C2-set / CD80-like C2-set immunoglobulin domain / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Programmed cell death 1 ligand 1
Similarity search - Component
Biological speciesHomo sapiens (human)
chemical production metagenome (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsLiu, K.F. / Xu, Z.P. / Han, P. / Pacesa, M. / Gao, G.F. / Chai, Y. / Tan, S.G.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92169208 China
CitationJournal: Nature / Year: 2023
Title: De novo design of protein interactions with learned surface fingerprints.
Authors: Pablo Gainza / Sarah Wehrle / Alexandra Van Hall-Beauvais / Anthony Marchand / Andreas Scheck / Zander Harteveld / Stephen Buckley / Dongchun Ni / Shuguang Tan / Freyr Sverrisson / Casper ...Authors: Pablo Gainza / Sarah Wehrle / Alexandra Van Hall-Beauvais / Anthony Marchand / Andreas Scheck / Zander Harteveld / Stephen Buckley / Dongchun Ni / Shuguang Tan / Freyr Sverrisson / Casper Goverde / Priscilla Turelli / Charlène Raclot / Alexandra Teslenko / Martin Pacesa / Stéphane Rosset / Sandrine Georgeon / Jane Marsden / Aaron Petruzzella / Kefang Liu / Zepeng Xu / Yan Chai / Pu Han / George F Gao / Elisa Oricchio / Beat Fierz / Didier Trono / Henning Stahlberg / Michael Bronstein / Bruno E Correia /
Abstract: Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even ...Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural data increase. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications. Here we use a geometric deep-learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features that are critical to drive protein-protein interactions. We hypothesized that these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof of principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1 and CTLA-4. Several designs were experimentally optimized, whereas others were generated purely in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling an approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function.
History
DepositionMar 17, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 12, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Database references / Category: citation / citation_author
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.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 10, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 17, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Programmed cell death 1 ligand 1
C: DBL2_02 binder
D: Programmed cell death 1 ligand 1
E: DBL2_02 binder
F: Programmed cell death 1 ligand 1
G: DBL2_02 binder
H: Programmed cell death 1 ligand 1
I: DBL2_02 binder


Theoretical massNumber of molelcules
Total (without water)157,5678
Polymers157,5678
Non-polymers00
Water0
1
A: Programmed cell death 1 ligand 1
C: DBL2_02 binder


Theoretical massNumber of molelcules
Total (without water)39,3922
Polymers39,3922
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Programmed cell death 1 ligand 1
E: DBL2_02 binder


Theoretical massNumber of molelcules
Total (without water)39,3922
Polymers39,3922
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
F: Programmed cell death 1 ligand 1
G: DBL2_02 binder


Theoretical massNumber of molelcules
Total (without water)39,3922
Polymers39,3922
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
H: Programmed cell death 1 ligand 1
I: DBL2_02 binder


Theoretical massNumber of molelcules
Total (without water)39,3922
Polymers39,3922
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)85.408, 116.084, 149.605
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

#1: Protein
Programmed cell death 1 ligand 1 / PD-L1 / PDCD1 ligand 1 / Programmed death ligand 1 / hPD-L1 / B7 homolog 1 / B7-H1


Mass: 27482.363 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD274, B7H1, PDCD1L1, PDCD1LG1, PDL1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NZQ7
#2: Protein
DBL2_02 binder


Mass: 11909.446 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) chemical production metagenome (others)
Production host: Escherichia coli (E. coli)

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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: 2.36 Å3/Da / Density % sol: 47.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.2 M potassium/sodium tartrate, 0.1 M Bis Tris propane, pH 6.5 ,20 % w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 23, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3→43.06 Å / Num. obs: 30347 / % possible obs: 99.4 % / Redundancy: 13 % / Biso Wilson estimate: 134.1 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.165 / Net I/σ(I): 12.8
Reflection shellResolution: 3→3.11 Å / Redundancy: 13.1 % / Rmerge(I) obs: 2.911 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2986 / CC1/2: 0.436 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3RRQ

3rrq


Resolution: 3→43.06 Å / SU ML: 0.5584 / Cross valid method: FREE R-VALUE / σ(F): 1.1 / Phase error: 38.4014
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2945 1513 5 %
Rwork0.2675 28771 -
obs0.2689 30284 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 134.14 Å2
Refinement stepCycle: LAST / Resolution: 3→43.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9316 0 0 0 9316
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00369456
X-RAY DIFFRACTIONf_angle_d0.701612770
X-RAY DIFFRACTIONf_chiral_restr0.04651473
X-RAY DIFFRACTIONf_plane_restr0.0061629
X-RAY DIFFRACTIONf_dihedral_angle_d16.00043597
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.10.47641340.46392554X-RAY DIFFRACTION99.67
3.1-3.210.43961370.40982598X-RAY DIFFRACTION99.71
3.21-3.340.42311350.39272580X-RAY DIFFRACTION99.34
3.34-3.490.39161360.36392588X-RAY DIFFRACTION99.71
3.49-3.670.35141350.31122563X-RAY DIFFRACTION99.08
3.67-3.90.34361380.28612618X-RAY DIFFRACTION99.57
3.9-4.20.32341370.26372604X-RAY DIFFRACTION99.78
4.2-4.620.24931380.23552629X-RAY DIFFRACTION99.68
4.63-5.290.24671390.22072638X-RAY DIFFRACTION99.96
5.29-6.660.29841400.25812670X-RAY DIFFRACTION99.79
6.66-43.060.23731440.22782729X-RAY DIFFRACTION97.32

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