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

• Published in: European journal of biochemistry Vol. 267; no. 17; pp. 5342 - 5355
• Main Authors: Sich, Christian, Improta, Sabina, Cowley, David John, Guenet, Chantal, Merly, Jean‐Pierre, Teufel, Michael, Saudek, Vladimir
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.09.2000
• Subjects: FKBP12; ligand binding; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; nerve regeneration; NMR structure; Protein Binding; protein dynamics; Tacrolimus Binding Protein 1A - chemistry; Tacrolimus Binding Protein 1A - metabolism
• ISSN: 0014-2956; 1432-1033
• DOI: 10.1046/j.1432-1327.2000.01551.x

The structure of a recently reported neurotrophic ligand, 3‐(3‐pyridyl)‐1‐propyl(2S)‐1‐(3,3‐dimethyl‐1,2‐dioxopentyl)‐2‐pyrrolidinecarboxylate, in complex with FKBP12 was determined using heteronuclear NMR spectroscopy. The inhibitor exhibits a binding mode analogous to that observed for the macrocycle FK506, used widely as an immunosuppressant, with the prolyl ring replacing the pipecolyl moiety and the amide bond in a trans conformation. However, fewer favourable protein–ligand interactions are detected in the structure of the complex, suggesting weaker binding compared with the immunosuppressant drug. Indeed, a micromolar dissociation constant was estimated from the NMR ligand titration profile, in contrast to the previously published nanomolar inhibition activity. Although the inhibitor possesses a remarkable structural simplicity with respect to FK506, 15N relaxation studies show that it induces similar effects on the protein dynamics, stabilizing the conformation of solvent‐exposed residues which are important for mediating the interaction of immunophilin/ligand complexes with molecular targets and potentially for the transmission of the neurotrophic action of FKBP12 inhibitors.