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- PDB-7xyq: Crystal strucutre of PD-L1 and the computationally designed DBL1_... -

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Basic information

Entry
Database: PDB / ID: 7xyq
TitleCrystal strucutre of PD-L1 and the computationally designed DBL1_03 protein binder
Components
  • CD274 molecule
  • DBL1_03
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 / negative regulation of CD4-positive, alpha-beta T cell proliferation / 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 ...: / 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 / negative regulation of CD4-positive, alpha-beta T cell proliferation / 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 / negative regulation of T cell proliferation / positive regulation of T cell proliferation / T cell costimulation / response to cytokine / recycling endosome membrane / actin cytoskeleton / early endosome membrane / cellular response to lipopolysaccharide / cell surface receptor signaling pathway / immune response / external side of plasma membrane / extracellular exosome / nucleoplasm
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
ARGININE / CD274 molecule
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsLiu, K. / Xu, Z. / Han, P. / Pacesa, M. / Gao, G.F. / Chai, Y. / Tan, S.
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
DepositionJun 2, 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.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CD274 molecule
B: DBL1_03
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9343
Polymers37,7592
Non-polymers1751
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1400 Å2
ΔGint-8 kcal/mol
Surface area16550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.930, 97.930, 106.110
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number94
Space group name H-MP42212
Space group name HallP4n2n
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/2
#3: y+1/2,-x+1/2,z+1/2
#4: x+1/2,-y+1/2,-z+1/2
#5: -x+1/2,y+1/2,-z+1/2
#6: -x,-y,z
#7: y,x,-z
#8: -y,-x,-z

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Components

#1: Protein CD274 molecule


Mass: 23757.910 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD274 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A2I2ZMM7
#2: Protein DBL1_03


Mass: 14001.120 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)
#3: Chemical ChemComp-ARG / ARGININE


Type: L-peptide linking / Mass: 175.209 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H15N4O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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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: 3.35 Å3/Da / Density % sol: 58.85 %
Crystal growTemperature: 291 K / Method: evaporation
Details: 0.02 M nickel (II) chloride hexahydrate, 0.02 M magnesium chloride hexahydrate, 0.02 M cadmium chloride hydrate, 0.1 M sodium acetate trihydrate, pH4.5, 24% w/v polyethylene glycol monomethylether 2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97889 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97889 Å / Relative weight: 1
ReflectionResolution: 2.85→48.97 Å / Num. obs: 12591 / % possible obs: 99.9 % / Observed criterion σ(F): 1.36 / Redundancy: 25.4 % / Biso Wilson estimate: 124.12 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.141 / Net I/σ(I): 20.7
Reflection shellResolution: 2.85→2.95 Å / Redundancy: 26.9 % / Rmerge(I) obs: 3.126 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1241 / CC1/2: 0.554 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.85→48.97 Å / SU ML: 0.5793 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 36.8818
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3182 630 5.01 %
Rwork0.2996 11952 -
obs0.3006 12582 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 124.12 Å2
Refinement stepCycle: LAST / Resolution: 2.85→48.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2619 0 0 1 2620
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00992658
X-RAY DIFFRACTIONf_angle_d1.2543589
X-RAY DIFFRACTIONf_chiral_restr0.0617417
X-RAY DIFFRACTIONf_plane_restr0.0095457
X-RAY DIFFRACTIONf_dihedral_angle_d6.8549347
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-3.070.41861230.41142336X-RAY DIFFRACTION99.96
3.07-3.380.38651240.38022344X-RAY DIFFRACTION99.92
3.38-3.870.40441230.35392345X-RAY DIFFRACTION99.96
3.87-4.870.34291260.28072398X-RAY DIFFRACTION99.96
4.87-48.970.25441340.26632529X-RAY DIFFRACTION99.85

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