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

Christian Wiesmann, Mark H. Ultsch, Steven H. Bass and Abraham M. de Vos ()
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Christian Wiesmann: Genentech, Inc.
Mark H. Ultsch: Genentech, Inc.
Steven H. Bass: Genentech, Inc.
Abraham M. de Vos: Genentech, Inc.

Nature, 1999, vol. 401, issue 6749, 184-188

Abstract: 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.

Date: 1999
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DOI: 10.1038/43705

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