Function
Tyrosine kinase receptor or high affinity nerve growth factor receptor (TRK-A) play an important role in cellular processes like growth, motility, differentiation and metabolism[1]. Nerve growth factor (NGF) is a neutrotrophin which binds with high affinity to TRK. The binding of NGF to TRK-A activates the latter which undergoes dimerization and autophosphorylation at several Tyr residues that selectively trigger activity in several intercellular signaling pathways via binding of specific effector proteins[2]. There are 3 members to the TRK family: TRK-A, TRK-B and TRK-C. All of them bind preferentially - NGF, neurotrophin-4, Brain-Derived Neurotrophic Factor (BDNF), and neurotrophin-3. See also:
Disease
Disregulation of TRK-A signalling leads to cancer.
Relevance
TRK-A inhibitors are suitable alternatives to teatment of neoendocrine tumors like pheochromocytomas and [3].
Structural highlights
TRK-A contains an extracellular ligand binding domain (LBD), a transmembrane helix and an intracellular region which contains the kinase domain. The kinase domain (PDB code 4yne) contains the tripeptide DFG which flips out in TRK-A inactivated form. (PDB code 4yne). Water molecules are shown as red spheres. The structure of the complex of TRK-A with the phenylpyrrolidine derivative shows the inhibitor forming hydrogen bonds to Met620 and Lys572 residues and π-π interactions of it with Phe617 and Phe 698 [4].
The (PDB code 2ifg) is a 2:2 dimer. The C-terminal immunoglobulin-like domain interacts with the NGF[5]. The extracellular domain of TRK-A contains flanked by (in yellow), 2 immunoglobulin-like domains and the nerve growth factor (NGF) binding domain.
