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Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor

Nature volume 401, pages 184–188 (1999)Cite this article

Abstract

Nerve growth factor (NGF) is involved in a variety of processes involving signalling, such as cell differentiation and survival, growth cessation and apoptosis of neurons1. These events are mediated by NGF as a result of binding to its two cell-surface receptors, TrkA and p75 (ref. 2). TrkA is a receptor with tyrosine kinase activity that forms a high-affinity binding site for NGF3. Of the five domains comprising its extracellular portion, the immunoglobulin-like domain proximal to the membrane (TrkA-d5 domain) is necessary and sufficient for NGF binding4. Here we present the crystal structure of human NGF in complex with human TrkA-d5 at 2.2 Å resolution. The ligand–receptor interface consists of two patches of similar size. One patch involves the central β-sheet that forms the core of the homodimeric NGF molecule and the loops at the carboxy-terminal pole of TrkA-d5. The second patch comprises the amino-terminal residues of NGF, which adopt a helical conformation upon complex formation, packing against the ‘ABED’ sheet of TrkA-d5. The structure is consistent with results from mutagenesis experiments for all neurotrophins, and indicates that the first patch may constitute a conserved binding motif for all family members, whereas the second patch is specific for the interaction between NGF and TrkA.

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Figure 1: Overall structure of the complex.
Figure 2: Sequence alignments.
Figure 3: The interface between NGF and TrkA-d5.

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Acknowledgements

We thank the following colleagues at Genentech: E. Martin and G. Burton for purified NGF; D. Reilly for fermentation runs; W. Henzel for N-terminal sequencing; J. Bourell for mass spectrometry analysis; H. Christinger for help with data collection; and L. Presta and D. Shelton for helpful discussions. We also thank the staff at SSRL, beam line 9-1, and ALS, beam line 5.2; and D. Dawbarn for sharing data before publication.

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  1. Departments of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Christian Wiesmann, Mark H. Ultsch & Abraham M. de Vos

  2. Departments of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Steven H. Bass

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  1. Christian Wiesmann
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Correspondence to Abraham M. de Vos.

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Wiesmann, C., Ultsch, M., Bass, S. et al. Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature 401, 184–188 (1999). https://doi.org/10.1038/43705

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