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

Research output: Contribution to journalArticle

Abstract

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. Shrestha et al. present a computational approach that employs a residue-based pharmacophore approach to design mutations for the interface of PD-1, specific to one of its cognate ligands only, 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.

Original languageEnglish (US)
Pages (from-to)829-836.e3
JournalStructure
Volume27
Issue number5
DOIs
StatePublished - May 7 2019

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Cell Death
Ligands
Programmed Cell Death 1 Receptor
T-Lymphocytes
Human Engineering
Proteins
Mutation
Therapeutics
Neoplasms

Keywords

  • programmed cell death-1
  • protein interface design
  • ProtLID
  • residue-specific pharmacophores

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Computational Redesign of PD-1 Interface for PD-L1 Ligand Selectivity. / Shrestha, Rojan; Garrett, Sarah C.; Almo, Steven C.; Fiser, Andras.

In: Structure, Vol. 27, No. 5, 07.05.2019, p. 829-836.e3.

Research output: Contribution to journalArticle

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