title: Solution structure of a neurotrophic ligand bound to FKBP12 and its effects on protein dynamics.
abstract: 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.
authors.affiliation: Department of Structural Biology and Cheminformatics, Department of Biotechnology, Sanofi-Synthelabo, Strasbourg, France.
authors.forename: C
authors.initials: C
authors.lastname: Sich
authors.forename: S
authors.initials: S
authors.lastname: Improta
authors.forename: D J
authors.initials: DJ
authors.lastname: Cowley
authors.forename: C
authors.initials: C
authors.lastname: Guenet
authors.forename: J P
authors.initials: JP
authors.lastname: Merly
authors.forename: M
authors.initials: M
authors.lastname: Teufel
authors.forename: V
authors.initials: V
authors.lastname: Saudek
mesh_terms: D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D022061:Tacrolimus Binding Protein 1A