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Crystal structure of the human 4-1BB/4-1BBL complex.
J Biol Chem. 2018 06 22; 293(25):9880-9891.JB

Abstract

4-1BBL is a member of the tumor necrosis factor (TNF) superfamily and is the ligand for the TNFR superfamily receptor, 4-1BB. 4-1BB plays an immunomodulatory role in T cells and NK cells, and agonists of this receptor have garnered strong attention as potential immunotherapy agents. Broadly speaking, the structural features of TNF superfamily members, their receptors, and ligand-receptor complexes are similar. However, a published crystal structure of human 4-1BBL suggests that it may be unique in this regard, exhibiting a three-bladed propeller-like trimer assembly that is distinctly different from that observed in other family members. This unusual structure also suggests that the human 4-1BB/4-1BBL complex may be structurally unique within the TNF/TNFR superfamily, but to date no structural data have been reported. Here we report the crystal structure of the human 4-1BB/4-1BBL complex at 2.4-Å resolution. In this structure, 4-1BBL does not adopt the unusual trimer assembly previously reported, but instead forms a canonical bell-shaped trimer typical of other TNF superfamily members. The structure of 4-1BB is also largely canonical as is the 4-1BB/4-1BBL complex. Mutational data support the 4-1BBL structure reported here as being biologically relevant, suggesting that the previously reported structure is not. Together, the data presented here offer insight into structure/function relationships in the 4-1BB/4-1BBL system and improve our structural understanding of the TNF/TNFR superfamily more broadly.

Authors+Show Affiliations

From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878 gilbrethr@medimmune.com.From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878.From the Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland 20878 Manuel.Baca@gilead.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

29720399

Citation

Gilbreth, Ryan N., et al. "Crystal Structure of the Human 4-1BB/4-1BBL Complex." The Journal of Biological Chemistry, vol. 293, no. 25, 2018, pp. 9880-9891.
Gilbreth RN, Oganesyan VY, Amdouni H, et al. Crystal structure of the human 4-1BB/4-1BBL complex. J Biol Chem. 2018;293(25):9880-9891.
Gilbreth, R. N., Oganesyan, V. Y., Amdouni, H., Novarra, S., Grinberg, L., Barnes, A., & Baca, M. (2018). Crystal structure of the human 4-1BB/4-1BBL complex. The Journal of Biological Chemistry, 293(25), 9880-9891. https://doi.org/10.1074/jbc.RA118.002803
Gilbreth RN, et al. Crystal Structure of the Human 4-1BB/4-1BBL Complex. J Biol Chem. 2018 06 22;293(25):9880-9891. PubMed PMID: 29720399.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structure of the human 4-1BB/4-1BBL complex. AU - Gilbreth,Ryan N, AU - Oganesyan,Vaheh Y, AU - Amdouni,Hamza, AU - Novarra,Shabazz, AU - Grinberg,Luba, AU - Barnes,Arnita, AU - Baca,Manuel, Y1 - 2018/05/02/ PY - 2018/03/08/received PY - 2018/5/4/pubmed PY - 2019/1/23/medline PY - 2018/5/4/entrez KW - T-cell biology KW - crystal structure KW - protein structure KW - protein-protein interaction KW - structural biology KW - structure-function KW - tumor necrosis factor (TNF) SP - 9880 EP - 9891 JF - The Journal of biological chemistry JO - J Biol Chem VL - 293 IS - 25 N2 - 4-1BBL is a member of the tumor necrosis factor (TNF) superfamily and is the ligand for the TNFR superfamily receptor, 4-1BB. 4-1BB plays an immunomodulatory role in T cells and NK cells, and agonists of this receptor have garnered strong attention as potential immunotherapy agents. Broadly speaking, the structural features of TNF superfamily members, their receptors, and ligand-receptor complexes are similar. However, a published crystal structure of human 4-1BBL suggests that it may be unique in this regard, exhibiting a three-bladed propeller-like trimer assembly that is distinctly different from that observed in other family members. This unusual structure also suggests that the human 4-1BB/4-1BBL complex may be structurally unique within the TNF/TNFR superfamily, but to date no structural data have been reported. Here we report the crystal structure of the human 4-1BB/4-1BBL complex at 2.4-Å resolution. In this structure, 4-1BBL does not adopt the unusual trimer assembly previously reported, but instead forms a canonical bell-shaped trimer typical of other TNF superfamily members. The structure of 4-1BB is also largely canonical as is the 4-1BB/4-1BBL complex. Mutational data support the 4-1BBL structure reported here as being biologically relevant, suggesting that the previously reported structure is not. Together, the data presented here offer insight into structure/function relationships in the 4-1BB/4-1BBL system and improve our structural understanding of the TNF/TNFR superfamily more broadly. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29720399/Crystal_structure_of_the_human_4_1BB/4_1BBL_complex_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)39970-1 DB - PRIME DP - Unbound Medicine ER -