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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.

SUBMITTER: Won EY

PROVIDER: S-EPMC2838339 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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The structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily.

Won Eun-Young EY Cha Kiweon K Byun Jung-Sue JS Kim Dong-Uk DU Shin Sumi S Ahn Byungchan B Kim Young Ho YH Rice Amanda J AJ Walz Thomas T Kwon Byoung S BS Cho Hyun-Soo HS

The Journal of biological chemistry 20091223 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 necros ...[more]

PMID: 20032458

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