Computational Redesign of PD-1 Interface for PD-L1 Ligand Selectivity

Structure. 2019 May 7;27(5):829-836.e3. doi: 10.1016/j.str.2019.03.006. Epub 2019 Mar 28.


Chronic or persistent stimulation of the programmed cell death-1 (PD-1) pathway prevents T cells from mounting anti-tumor and anti-viral immune responses. Blockade of this inhibitory checkpoint pathway has shown therapeutic importance by rescuing T cells from their exhausted state. Cognate ligands of the PD-1 receptor include the tissue-specific PD-L1 and PD-L2 proteins. Engineering a human PD-1 interface specific for PD-L1 or PD-L2 can provide a specific reagent and therapeutic advantage for tissue-specific disruption of the PD-1 pathway. We utilized ProtLID, a computational framework, which constitutes a residue-based pharmacophore approach, to custom-design a human PD-1 interface specific to human PD-L1 without any significant affinity to PD-L2. In subsequent cell assay experiments, half of all single-point mutant designs proved to introduce a statistically significant selectivity, with nine of these maintaining a close to wild-type affinity to PD-L1. This proof-of-concept study suggests a general approach to re-engineer protein interfaces for specificity.

Keywords: ProtLID; programmed cell death-1; protein interface design; residue-specific pharmacophores.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B7-H1 Antigen / chemistry*
  • B7-H1 Antigen / genetics
  • Computer Simulation
  • Female
  • Flow Cytometry
  • HEK293 Cells
  • Humans
  • Immune System
  • Ligands
  • Mice
  • Molecular Conformation
  • Mutagenesis, Site-Directed
  • Mutation
  • Point Mutation*
  • Programmed Cell Death 1 Receptor / chemistry*
  • Programmed Cell Death 1 Receptor / genetics
  • Protein Domains
  • Protein Engineering*
  • Protein Interaction Mapping
  • T-Lymphocytes / metabolism


  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Ligands
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor