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 language | English (US) |
|---|---|
| Pages (from-to) | 829-836.e3 |
| Journal | Structure |
| Volume | 27 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 7 2019 |
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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 journal › Article
}
TY - JOUR
T1 - Computational Redesign of PD-1 Interface for PD-L1 Ligand Selectivity
AU - Shrestha, Rojan
AU - Garrett, Sarah C.
AU - Almo, Steven C.
AU - Fiser, Andras
PY - 2019/5/7
Y1 - 2019/5/7
N2 - 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.
AB - 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.
KW - programmed cell death-1
KW - protein interface design
KW - ProtLID
KW - residue-specific pharmacophores
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UR - http://www.scopus.com/inward/citedby.url?scp=85064855159&partnerID=8YFLogxK
U2 - 10.1016/j.str.2019.03.006
DO - 10.1016/j.str.2019.03.006
M3 - Article
VL - 27
SP - 829-836.e3
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 5
ER -