Molecular determinants of signal transduction in tropomyosin receptor kinases

Tropomyosin receptor kinase (Trk) receptors are essential regulators of neuronal development, survival, and plasticity through their interactions with neurotrophins. This review examines the structural and molecular mechanisms connecting ligand binding to the diverse signaling outcomes of Trk receptors. We analyze how neurotrophin binding and allosteric interactions trigger conformational changes that activate distinct signaling pathways. Our discussion explores how allosteric modulation-binding of ligands to sites distinct from the primary receptor site-and ligand bias-where different neurotrophins binding the same receptor preferentially activate certain downstream pathways-may together shape receptor function, focusing on structural and conformational mechanisms. Despite recent advances, important structural details remain unresolved. Further insights into Trk receptor structure and dynamics could significantly enhance therapeutic development by enabling the design of drugs that selectively target-specific signaling pathways.