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

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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.