title: The structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily.
abstract: 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.
authors.affiliation: Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Won
authors.forename: Kiweon
authors.initials: K
authors.lastname: Cha
authors.forename: Jung-Sue
authors.initials: JS
authors.lastname: Byun
authors.forename: Dong-Uk
authors.initials: DU
authors.lastname: Kim
authors.forename: Sumi
authors.initials: S
authors.lastname: Shin
authors.forename: Byungchan
authors.initials: B
authors.lastname: Ahn
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Rice
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
mesh_terms: D053330:4-1BB Ligand / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D049109:Cell Proliferation; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D005434:Flow Cytometry; D006801:Humans; D008854:Microscopy, Electron / Q000379:methods; D008958:Models, Molecular; D008968:Molecular Conformation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000737:chemistry / Q000502:physiology*
chemical_list: D053330:4-1BB Ligand; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9