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
N1 - Funding Information:
This work was supported by NIH grants R01 GM118709 , R01 HG008325 , R01 AI141816 , and the Extreme Science and Engineering Discovery Environment (XSEDE) project ( NSF grant ACI-1053575 ).
Funding Information:
This work was supported by NIH grants R01 GM118709, R01 HG008325, R01 AI141816, and the Extreme Science and Engineering Discovery Environment (XSEDE) project (NSF grant ACI-1053575). Conceptualization, A.F. Methodology and Formal Analysis, R.S. and A.F. Investigation, S.C.G. and S.C.A. Writing, R.S. A.F. and S.A. Supervision and Project Administration, A.F. A provisional patent application has been filed. US Patent Application no. 62/736,477.
Publisher Copyright:
© 2019 Elsevier Ltd
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 - ProtLID
KW - programmed cell death-1
KW - protein interface design
KW - residue-specific pharmacophores
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U2 - 10.1016/j.str.2019.03.006
DO - 10.1016/j.str.2019.03.006
M3 - Article
C2 - 30930066
AN - SCOPUS:85064855159
VL - 27
SP - 829-836.e3
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 5
ER -