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- PDB-7dy7: Discovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis t... -

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Basic information

Entry
Database: PDB / ID: 7dy7
TitleDiscovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis that Promotes PD-L1 Internalization and Degradation
ComponentsProgrammed cell death 1 ligand 1
KeywordsIMMUNOSUPPRESSANT / Immune checkpoint / Inhibitor / Complex / Dimer
Function / homology
Function and homology information


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 T cell mediated immune response to tumor cell / 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 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 T cell mediated immune response to tumor cell / 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 / receptor ligand activity / 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
Chem-HOU / Programmed cell death 1 ligand 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 Å
AuthorsCheng, Y. / Wang, T.Y. / Lu, M.L. / Jiang, S. / Xiao, Y.B.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation.
Authors: Wang, T. / Cai, S. / Cheng, Y. / Zhang, W. / Wang, M. / Sun, H. / Guo, B. / Li, Z. / Xiao, Y. / Jiang, S.
History
DepositionJan 20, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2022Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Programmed cell death 1 ligand 1
A: Programmed cell death 1 ligand 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,2053
Polymers28,8052
Non-polymers4001
Water724
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)134.570, 32.682, 73.603
Angle α, β, γ (deg.)90.000, 103.960, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: HIS / End label comp-ID: HIS / Auth seq-ID: 18 - 143 / Label seq-ID: 1 - 126

Dom-IDSelection detailsAuth asym-IDLabel asym-ID
1chain AAB
2chain BBA

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Components

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


Mass: 14402.465 Da / Num. of mol.: 2
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: Chemical ChemComp-HOU / 2-[[3-[[5-(2-methyl-3-phenyl-phenyl)-1,3,4-oxadiazol-2-yl]amino]phenyl]methylamino]ethanol


Mass: 400.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.73 Å3/Da / Density % sol: 54.89 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop / Details: PEG 3350,ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 13, 2020
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.42→23.472 Å / Num. obs: 22861 / % possible obs: 99.08 % / Redundancy: 6.3 % / CC1/2: 0.986 / Rmerge(I) obs: 0.1144 / Rrim(I) all: 0.1253 / Net I/σ(I): 9.83
Reflection shellResolution: 2.42→2.506 Å / Num. unique obs: 1230 / CC1/2: 0.701 / % possible all: 99.59

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5C3T

5c3t


Resolution: 2.42→23.472 Å / SU ML: 0.48 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2396 953 4.17 %
Rwork0.1964 21908 -
obs0.1982 22861 98.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 184.37 Å2 / Biso mean: 78.6091 Å2 / Biso min: 42.99 Å2
Refinement stepCycle: final / Resolution: 2.42→23.472 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2024 0 54 4 2082
Biso mean--80.22 72.22 -
Num. residues----252
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082101
X-RAY DIFFRACTIONf_angle_d0.932844
X-RAY DIFFRACTIONf_chiral_restr0.053312
X-RAY DIFFRACTIONf_plane_restr0.006359
X-RAY DIFFRACTIONf_dihedral_angle_d18.5281253
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1135X-RAY DIFFRACTION19.211TORSIONAL
12B1135X-RAY DIFFRACTION19.211TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.42-2.54750.46721380.4213315499
2.5475-2.70690.38011360.3601316098
2.7069-2.91550.31981340.2736310099
2.9155-3.20820.26141430.2505319399
3.2082-3.6710.3071410.2203306697
3.671-4.61920.19531360.1679313299
4.6192-23.4720.17691250.1391310398
Refinement TLS params.Method: refined / Origin x: 139.7685 Å / Origin y: -8.37 Å / Origin z: 24.0775 Å
111213212223313233
T0.6129 Å2-0.053 Å2-0.0387 Å2-0.4743 Å2-0.0138 Å2--0.5474 Å2
L1.4038 °2-0.2913 °2-0.4504 °2-1.1927 °20.3105 °2--3.5959 °2
S0.0748 Å °-0.1176 Å °0.1132 Å °-0.0768 Å °0.0269 Å °-0.1527 Å °-0.0519 Å °0.3301 Å °-0.1126 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allB18 - 143
2X-RAY DIFFRACTION1allA18 - 143
3X-RAY DIFFRACTION1allC1
4X-RAY DIFFRACTION1allS1 - 4

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