Solution structure of a neurotrophic ligand bound to FKBP12 and its effects on protein dynamics

The structure of a recently reported neurotrophic ligand, 3-(3-pyridyl)-1-p ropyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, in com plex with FKBP12 was determined using heteronuclear NMR spectroscopy. The i nhibitor exhibits a binding mode analogous to that observed for the macrocy cle FK506, used widely as an immunosuppressant, with the prolyl ring replac ing the pipecolyl moiety and the amide bond in a trans conformation. Howeve r, fewer favourable protein-ligand interactions are detected in the structu re of the complex, suggesting weaker binding compared with the immunosuppre ssant drug. Indeed, a micromolar dissociation constant was estimated from t he NMR ligand titration profile, in contrast to the previously published na nomolar inhibition activity. Although the inhibitor possesses a remarkable structural simplicity with respect to FK506, N-15 relaxation studies show t hat it induces similar effects on the protein dynamics, stabilizing the con formation of solvent-exposed residues which are important for mediating the interaction of immunophilin/ligand complexes with molecular targets and po tentially for the transmission of the neurotrophic action of FKBP12 inhibit ors.