ArticleThe Journal of biological chemistry2018
Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.The Journal of allergy and clinical immunology · 2019Trial
- FTL008.16, a 5T4-Conditional 4-1BB bispecific antibody, potently enhances antitumor immunity via tumor-directed t-cell activation.Oncoimmunology · 2026Article
- Molecular mechanistic insights into the OX40-OX40L complex from biophysical and computational analyses.Protein science : a publication of the Protein Society · 2026Article
- An amphiregulin reporter mouse enables transcriptional and clonal expansion analysis of reparative lung Tregs.JCI insight · 2025Article
- Clinical and functional characterization of a novelFrontiers in immunology · 2025Article
- Exploring the role of APRIL in autoimmunity: implications for therapeutic targeting in systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome.Frontiers in immunology · 2025Review
- Characterization of a Trispecific PD-L1 Blocking Antibody That Exhibits EGFR-Conditional 4-1BB Agonist Activity.Antibodies (Basel, Switzerland) · 2024Article
- 4-1BB immunotherapy: advances and hurdles.Experimental & molecular medicine · 2024Review
- Rehabilitation: Neurogenic Bone Loss after Spinal Cord Injury.Biomedicines · 2023Review
- An Fc-muted bispecific antibody targeting PD-L1 and 4-1BB induces antitumor immune activity in colorectal cancer without systemic toxicity.Cellular & molecular biology letters · 2023Article
- Agonism of 4-1BB for immune therapy: a perspective on possibilities and complications.Frontiers in immunology · 2023Review
- A novel 4-1BB/HER2 bispecific antibody shows potent antitumor activities by increasing and activating tumor-infiltrating T cells.American journal of cancer research · 2023Article
- The Glycosylation of Immune Checkpoints and Their Applications in Oncology.Pharmaceuticals (Basel, Switzerland) · 2022Review
- A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis.Signal transduction and targeted therapy · 2022Article
- Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering.Communications biology · 2022Article
- An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.Nature cancer · 2022Article
- Article
- Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity.Nature communications · 2021Article
- A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains.Nature reviews. Clinical oncology · 2021Review
- Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex.The Journal of biological chemistry · 2021Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Human (h)4-1BB (TNFRSF9 or CD137) is an inducible tumor necrosis factor receptor (TNFR) superfamily member that interacts with its cognate ligand h4-1BBL to promote T lymphocyte activation and proliferation. h4-1BB is currently being targeted with agonists in cancer immunotherapy. Here, we determined the crystal structures of unbound h4-1BBL and both WT h4-1BB and a dimerization-deficient h4-1BB mutant (C121S) in complex with h4-1BBL at resolutions between 2.7 and 3.2 Å. We observed that the structural arrangement of 4-1BBL, both unbound and in the complex, represents the canonical bell shape as seen in other similar TNF proteins and differs from the previously reported three-bladed propeller structure of 4-1BBL. We also found that the binding site for the receptor is at the crevice formed between two protomers of h4-1BBL, but that h4-1BB interacts predominantly with only one ligand protomer. Moreover, h4-1BBL lacked the conserved tyrosine residue in the DE loop that forms canonical interactions between other TNFR family molecules and their ligands, suggesting h4-1BBL engages h4-1BB through a distinct mechanism. Of note, we discovered that h4-1BB forms a disulfide-linked dimer because of the presence of an additional cysteine residue found in its cysteine-rich domain 4 (CRD4). As a result, h4-1BB dimerization, in addition to trimerization via h4-1BBL binding, could result in cross-linking of individual ligand-receptor complexes to form a 2D network that stimulates strong h4-1BB signaling. This work provides critical insights into the structural and functional properties of both h4-1BB and h4-1BBL and reveals that covalent receptor dimerization amplifies h4-1BB signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.