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- PDB-8k5n: Discovery of Novel PD-L1 Inhibitors That Induce Dimerization and ... -

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Basic information

Entry
Database: PDB / ID: 8k5n
TitleDiscovery of Novel PD-L1 Inhibitors That Induce Dimerization and Degradation of PD-L1 Based on Fragment Coupling Strategy
ComponentsProgrammed cell death 1 ligand 1
KeywordsIMMUNE SYSTEM / Immune checkpoint / Dimer / Small molecule inhibitor
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 / negative regulation of type II interferon 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 / negative regulation of type II interferon production / positive regulation of interleukin-10 production / Co-inhibition by PD-1 / positive regulation of T cell proliferation / negative regulation of T cell proliferation / T cell costimulation / response to cytokine / recycling endosome membrane / actin cytoskeleton / cellular response to lipopolysaccharide / early endosome membrane / adaptive immune response / transcription coactivator activity / cell surface receptor signaling pathway / immune response / positive regulation of cell migration / receptor ligand activity / 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-I7M / Programmed cell death 1 ligand 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsCheng, Y. / Xiao, Y.B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.
Authors: Wang, K. / Zhang, X. / Cheng, Y. / Qi, Z. / Ye, K. / Zhang, K. / Jiang, S. / Liu, Y. / Xiao, Y. / Wang, T.
History
DepositionJul 22, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 9, 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
A: Programmed cell death 1 ligand 1
B: Programmed cell death 1 ligand 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,0753
Polymers29,3582
Non-polymers7181
Water2,144119
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)49.250, 49.250, 278.030
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number95
Space group name H-MP4322
Components on special symmetry positions
IDModelComponents
11A-250-

HOH

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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: 14678.759 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 B (bacteria) / References: UniProt: Q9NZQ7
#2: Chemical ChemComp-I7M / 3-[(1~{S})-1-[6-methoxy-3-methyl-5-[[[(2~{S})-5-oxidanylidenepyrrolidin-2-yl]methylamino]methyl]pyridin-2-yl]oxy-2,3-dihydro-1~{H}-inden-4-yl]-2-methyl-~{N}-[5-[[[(2~{S})-5-oxidanylidenepyrrolidin-2-yl]methylamino]methyl]pyridin-2-yl]benzamide


Mass: 717.856 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H47N7O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.87 Å3/Da / Density % sol: 57.16 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop / Details: Ammonium acetate, PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.2→19.62 Å / Num. obs: 18409 / % possible obs: 99.09 % / Redundancy: 24.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.1603 / Net I/σ(I): 21.38
Reflection shellResolution: 2.2→2.279 Å / Rmerge(I) obs: 1.218 / Mean I/σ(I) obs: 3.73 / Num. unique obs: 1754 / CC1/2: 0.967

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→19.62 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2345 1834 9.98 %
Rwork0.1969 --
obs0.2006 18382 99.36 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→19.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1850 0 53 119 2022
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071941
X-RAY DIFFRACTIONf_angle_d0.9512628
X-RAY DIFFRACTIONf_dihedral_angle_d8.707268
X-RAY DIFFRACTIONf_chiral_restr0.06293
X-RAY DIFFRACTIONf_plane_restr0.008330
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.260.3141360.24411229X-RAY DIFFRACTION98
2.26-2.330.30941330.24421231X-RAY DIFFRACTION99
2.33-2.40.26891360.22191221X-RAY DIFFRACTION99
2.4-2.490.34411380.21581241X-RAY DIFFRACTION99
2.49-2.590.26321380.22951247X-RAY DIFFRACTION99
2.59-2.70.2741380.23111245X-RAY DIFFRACTION99
2.7-2.850.26231360.22321237X-RAY DIFFRACTION100
2.85-3.020.26561430.21591273X-RAY DIFFRACTION99
3.02-3.250.26051420.23441274X-RAY DIFFRACTION100
3.26-3.580.24141410.2081281X-RAY DIFFRACTION100
3.58-4.090.19541470.17781318X-RAY DIFFRACTION100
4.1-5.140.19141450.15281306X-RAY DIFFRACTION100
5.15-19.620.19021610.16841445X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -18.4112 Å / Origin y: 21.3254 Å / Origin z: -14.3235 Å
111213212223313233
T0.163 Å2-0.0264 Å20.0226 Å2-0.3129 Å2-0.0318 Å2--0.2234 Å2
L0.6371 °2-0.294 °20.1414 °2-0.9818 °2-0.6467 °2--3.0991 °2
S-0.0349 Å °-0.1599 Å °0.0613 Å °-0.0109 Å °0.0268 Å °-0.0611 Å °-0.0302 Å °0.1368 Å °0.0281 Å °
Refinement TLS groupSelection details: all

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