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Structure of the TRAIL–DR5 complex reveals mechanisms conferring specificity in apoptotic initiation

Nature Structural Biology volume 6, pages 1048–1053 (1999)Cite this article

Abstract

TRAIL, an apoptosis inducing ligand, has at least four cell surface receptors including the death receptor DR5. Here we report the crystal structure at 2.2 Å resolution of a complex between TRAIL and the extracellular region of DR5. TRAIL forms a central homotrimer around which three DR5 molecules bind. Radical differences in the surface charge of the ligand, together with variation in the alignment of the two receptor domains confer specificity between members of these ligand and receptor families. The existence of a switch mechanism allowing variation in receptor domain alignment may mean that it is possible to engineer receptors with multiple specificities by exploiting contact positions unique to individual receptor–ligand pairs.

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Figure 1: The structure of TRAIL, DR5 and the TRAIL–DR5 complex.
Figure 2: Comparison of the TRAIL–DR5 and TNFβ–TNF-R1 complexes.
Figure 3: Elements of conservation and specificity in ligand–receptor binding.

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Acknowledgements

We thank R. Esnouf, P. Gouet and R. Bryan for computing facilities and programs, K. Harlos for help with heavy atom soaks, G. Gao for advice on refolding protocols and crystallisation trials, K. Hudson and J. Heath for the rhinovirus 3c protease methodology, M. Gross for circular dichroism analysis, A. van der Merwe and A. McMichael for discussion. We also thank the staff at the European Molecular Biology Laboratory outstation, ID2 (ESRF, Grenoble) and at 9.6 (SRS, Daresbury). JM is funded by Siriraj Hospital Mahidol University Thailand, EYJ is funded by the Royal Society and the Cancer Research Campaign, GRS and DIS are funded by the MRC.

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Authors and Affiliations

  1. MRC Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK

    Juthathip Mongkolsapaya, Nan Chen, Xiao-Ning Xu & Gavin R. Screaton

  2. Structural Biology, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK

    Jonathan M. Grimes, David I. Stuart & E.Yvonne Jones

  3. Oxford Centre for Molecular Sciences, New Chemistry Building, South Parks Road, Oxford, OX1 3QT, UK

    David I. Stuart & E.Yvonne Jones

  4. Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Gavin R. Screaton

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  1. Juthathip Mongkolsapaya
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Correspondence to E.Yvonne Jones.

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Mongkolsapaya, J., Grimes, J., Chen, N. et al. Structure of the TRAIL–DR5 complex reveals mechanisms conferring specificity in apoptotic initiation. Nat Struct Mol Biol 6, 1048–1053 (1999). https://doi.org/10.1038/14935

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