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Crystal structure of TNFα complexed with a poxvirus MHC-related TNF binding protein

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Abstract

The poxvirus 2L protein binds tumor necrosis factor-α (TNFα) to inhibit host antiviral and immune responses. The 2.8-Å 2L–TNFα structure reveals three symmetrically arranged 2L molecules per TNFα trimer. 2L resembles class I major histocompatibility complex (MHC) molecules but lacks a peptide-binding groove and β2-microglobulin light chain. Overlap between the 2L and host TNF receptor-binding sites on TNFα rationalizes 2L inhibition of TNFα–TNF receptor interactions and prevention of TNFα-induced immune responses.

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Figure 1: Structure of 2L–TNFα and comparison with TNFR1–TNFβ.
Figure 2: The 2L–TNFα interface.

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Acknowledgements

Diffraction data were collected at the Stanford Synchrotron Radiation Laboratory. We thank the Caltech Protein Expression Center and the Gordon and Betty Moore Foundation for support of the Molecular Observatory at Caltech. This work was supported by a Life Sciences Research Foundation Fellowship (Z.Y.) and the Howard Hughes Medical Institute.

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Author notes

  1. Present address: Beijing Novo Nordisk Pharmaceuticals Science and Technology Co., Ltd., Changping District, Beijing, China.

  2. Anthony P West: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biology 114-96, California Institute of Technology, Pasadena, California, USA

    Zhiru Yang, Anthony P West Jr & Pamela J Bjorkman

  2. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA

    Pamela J Bjorkman

Authors
  1. Zhiru Yang
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  2. Anthony P West Jr
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  3. Pamela J Bjorkman
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Contributions

Z.Y. and A.P.W. performed the experiments; Z.Y., A.P.W. and P.J.B. analyzed and interpreted that data; P.J.B. oversaw the project.

Corresponding author

Correspondence to Pamela J Bjorkman.

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Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1–5 (PDF 4201 kb)

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Yang, Z., West, A. & Bjorkman, P. Crystal structure of TNFα complexed with a poxvirus MHC-related TNF binding protein. Nat Struct Mol Biol 16, 1189–1191 (2009). https://doi.org/10.1038/nsmb.1683

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