Noncompetitive Allosteric Antagonism of Death Receptor 5 by a Synthetic Affibody Ligand.
Journal
Biochemistry
ISSN: 1520-4995
Titre abrégé: Biochemistry
Pays: United States
ID NLM: 0370623
Informations de publication
Date de publication:
13 10 2020
13 10 2020
Historique:
pubmed:
18
9
2020
medline:
23
3
2021
entrez:
17
9
2020
Statut:
ppublish
Résumé
Fatty acid-induced upregulation of death receptor 5 (DR5) and its cognate ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), promotes hepatocyte lipoapoptosis, which is a key mechanism in the progression of fatty liver disease. Accordingly, inhibition of DR5 signaling represents an attractive strategy for treating fatty liver disease. Ligand competition strategies are prevalent in tumor necrosis factor receptor antagonism, but recent studies have suggested that noncompetitive inhibition through perturbation of the receptor conformation may be a compelling alternative. To this end, we used yeast display and a designed combinatorial library to identify a synthetic 58-amino acid affibody ligand that specifically binds DR5. Biophysical and biochemical studies show that the affibody neither blocks TRAIL binding nor prevents the receptor-receptor interaction. Live-cell fluorescence lifetime measurements indicate that the affibody induces a conformational change in transmembrane dimers of DR5 and favors an inactive state of the receptor. The affibody inhibits apoptosis in TRAIL-treated Huh-7 cells, an
Identifiants
pubmed: 32941010
doi: 10.1021/acs.biochem.0c00529
pmc: PMC7658720
mid: NIHMS1643723
doi:
Substances chimiques
Ligands
0
Peptides
0
Receptors, TNF-Related Apoptosis-Inducing Ligand
0
TNF-Related Apoptosis-Inducing Ligand
0
TNFRSF10B protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3856-3868Subventions
Organisme : NIAID NIH HHS
ID : R21 AI144932
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB028274
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK041876
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB023339
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM131814
Pays : United States
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