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

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

Author information

1
Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
2
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
3
Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Electronic address: andras.fiser@einstein.yu.edu.

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.

KEYWORDS:

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

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