biostudies-literatureWon EYNIEHS NIH HHSNIGMS NIH HHS9202-10https://www.ebi.ac.uk/biostudies/studies/S-EPMC2838339biostudies-literatureUnknown285(12)Binding of the 4-1BB ligand (4-1BBL) to its receptor, 4-1BB, provides the T lymphocyte with co-stimulatory signals for survival, proliferation, and differentiation. Importantly, the 4-1BB-4-1BBL pathway is a well known target for anti-cancer immunotherapy. Here we present the 2.3-A crystal structure of the extracellular domain of human 4-1BBL. The ectodomain forms a homotrimer with an extended, three-bladed propeller structure that differs from trimers formed by other members of the tumor necrosis factor (TNF) superfamily. Based on the 4-1BBL structure, we modeled its complex with 4-1BB, which was consistent with images obtained by electron microscopy, and verified the binding site by site-directed mutagenesis. This structural information will facilitate the development of immunotherapeutics targeting 4-1BB.The Journal of biological chemistryThe structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily.PMC283833927301C0040P01 GM062580GM62580Shin SCho HSByun JSWalz TKwon BSKim YHCha KKim DUWon EYAhn BRice AJfalseThe structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily.Binding of the 4-1BB ligand (4-1BBL) to its receptor, 4-1BB, provides the T lymphocyte with co-stimulatory signals for survival, proliferation, and differentiation. Importantly, the 4-1BB-4-1BBL pathway is a well known target for anti-cancer immunotherapy. Here we present the 2.3-A crystal structure of the extracellular domain of human 4-1BBL. The ectodomain forms a homotrimer with an extended, three-bladed propeller structure that differs from trimers formed by other members of the tumor necrosis factor (TNF) superfamily. Based on the 4-1BBL structure, we modeled its complex with 4-1BB, which was consistent with images obtained by electron microscopy, and verified the binding site by site-directed mutagenesis. This structural information will facilitate the development of immunotherapeutics targeting 4-1BB.2010-01-01T00:00:00Z2010 Mar2020-11-19T12:41:28Z2019-03-27T00:29:22ZS-EPMC28383392003245810.1074/jbc.M109.08444210.1074/jbc.m109.084442