5O45

Structure of human PD-L1 in complex with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.99 Å
  • R-Value Free: 0.137 
  • R-Value Work: 0.112 
  • R-Value Observed: 0.114 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint.

Magiera-Mularz, K.Skalniak, L.Zak, K.M.Musielak, B.Rudzinska-Szostak, E.Kocik, J.Grudnik, P.Sala, D.Zarganes-Tzitzikas, T.Shaabani, S.Domling, A.Dubin, G.Holak, T.A.

(2017) Angew Chem Int Ed Engl 56: 13732-13735

  • DOI: https://doi.org/10.1002/anie.201707707
  • Primary Citation of Related Structures:  
    5O45, 5O4Y

  • PubMed Abstract: 

    Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway.


  • Organizational Affiliation

    Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Krakow, Poland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Programmed cell death 1 ligand 1129Homo sapiensMutation(s): 0 
Gene Names: CD274B7H1PDCD1L1PDCD1LG1PDL1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NZQ7 (Homo sapiens)
Explore Q9NZQ7 
Go to UniProtKB:  Q9NZQ7
PHAROS:  Q9NZQ7
GTEx:  ENSG00000120217 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NZQ7
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
PHE-MEA-9KK-SAR-ASP-VAL-MEA-TYR-SAR-TRP-TYR-LEU-CCS-GLY-NH215synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  3 Unique
IDChains TypeFormula2D DiagramParent
CCS
Query on CCS
B
L-PEPTIDE LINKINGC5 H9 N O4 SCYS
MEA
Query on MEA
B
L-PEPTIDE LINKINGC10 H13 N O2PHE
SAR
Query on SAR
B
PEPTIDE LINKINGC3 H7 N O2GLY
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.99 Å
  • R-Value Free: 0.137 
  • R-Value Work: 0.112 
  • R-Value Observed: 0.114 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 31.814α = 90
b = 53.682β = 90
c = 80.926γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Science CenterPolandUMO-2014/12/W/NZ1/00457
European CommissionPolandMarie Curie FP7-Reintegration-Grant
National Science CenterPolandUMO-2012/07/E/NZ1/01907

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-20
    Type: Initial release
  • Version 1.1: 2017-10-25
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description