TY - JOUR
T1 - Decoy strategies
T2 - The structure of TL1A:DcR3 complex
AU - Zhan, Chenyang
AU - Patskovsky, Yury
AU - Yan, Qingrong
AU - Li, Zhenhong
AU - Ramagopal, Udupi
AU - Cheng, Huiyong
AU - Brenowitz, Michael
AU - Hui, Xiao
AU - Nathenson, Stanley G.
AU - Almo, Steven C.
N1 - Funding Information:
We gratefully acknowledge the staff of the X29 beamline at the National Synchrotron Light Source, and the staff of the 24-ID-E beamline at the Advanced Photon Source. This work was supported by National Institutes of Health Grant AI07289 (to S.G.N. and S.C.A.), the Albert Einstein Cancer Center Grant (National Cancer Institute, P30CA13330), and the Albert Einstein College of Medicine Macromolecular Therapeutics Development Facility.
PY - 2011/2/9
Y1 - 2011/2/9
N2 - Decoy Receptor 3 (DcR3), a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily, neutralizes three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands engages unique signaling receptors which direct distinct and critical immune responses. We report the crystal structures of the unliganded DcR3 ectodomain and its complex with TL1A, as well as complementary mutagenesis and biochemical studies. These analyses demonstrate that DcR3 interacts with invariant backbone and side-chain atoms in the membrane-proximal half of TL1A which supports recognition of its three distinct TNF ligands. Additional features serve as antideterminants that preclude interaction with other members of the TNF superfamily. This mode of interaction is unique among characterized TNF:TNFR family members and provides a mechanistic basis for the broadened specificity required to support the decoy function of DcR3, as well as for the rational manipulation of specificity and affinity of DcR3 and its ligands.
AB - Decoy Receptor 3 (DcR3), a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily, neutralizes three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands engages unique signaling receptors which direct distinct and critical immune responses. We report the crystal structures of the unliganded DcR3 ectodomain and its complex with TL1A, as well as complementary mutagenesis and biochemical studies. These analyses demonstrate that DcR3 interacts with invariant backbone and side-chain atoms in the membrane-proximal half of TL1A which supports recognition of its three distinct TNF ligands. Additional features serve as antideterminants that preclude interaction with other members of the TNF superfamily. This mode of interaction is unique among characterized TNF:TNFR family members and provides a mechanistic basis for the broadened specificity required to support the decoy function of DcR3, as well as for the rational manipulation of specificity and affinity of DcR3 and its ligands.
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U2 - 10.1016/j.str.2010.12.004
DO - 10.1016/j.str.2010.12.004
M3 - Article
C2 - 21300286
AN - SCOPUS:79551711871
SN - 0969-2126
VL - 19
SP - 162
EP - 171
JO - Structure
JF - Structure
IS - 2
ER -