The 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.
Won
Eun-Young
EY
Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Korea.
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
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*
D053330:4-1BB Ligand; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9