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

Nature | Sep 9, 1999

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.

Pubmed ID: 10490030 RIS Download

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 | Protein Conformation | Proto-Oncogene Proteins | Receptor Protein-Tyrosine Kinases | Receptor, trkA | Receptors, Nerve Growth Factor | Recombinant Proteins | Sequence Homology, Amino Acid