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

Correspondence to: Abraham M. de Vos¹ Correspondence and requests for materials should be directed to A.M.D.V. (e-mail: Email: devos@gene.com). The coordinates have been deposited with the Protein Data Bank for immediate release (accession number 1www).

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 -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.