Crystal Structure of Nerve Growth Factor in Complex With the Ligand-Binding Domain of the TrkA Receptor

Nature. 1999 Sep 9;401(6749):184-8. doi: 10.1038/43705.

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 neurons. These events are mediated by NGF as a result of binding to its two cell-surface receptors, TrkA and p75. TrkA is a receptor with tyrosine kinase activity that forms a high-affinity binding site for NGF. 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 binding. Here we present the crystal structure of human NGF in complex with human TrkA-d5 at 2.2 A resolution. The ligand-receptor interface consists of two patches of similar size. One patch involves the central beta-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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Escherichia coli
  • Humans
  • Ligands
  • Macromolecular Substances
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Nerve Growth Factors / chemistry*
  • Nerve Growth Factors / metabolism
  • Protein Conformation
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / chemistry*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, trkA
  • Receptors, Nerve Growth Factor / chemistry*
  • Receptors, Nerve Growth Factor / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid

Substances

  • Ligands
  • Macromolecular Substances
  • Nerve Growth Factors
  • Proto-Oncogene Proteins
  • Receptors, Nerve Growth Factor
  • Recombinant Proteins
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkA

Associated data

  • PDB/1WWW