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-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.
Sich
C
C
Department of Structural Biology and Cheminformatics, Department of Biotechnology, Sanofi-Synthelabo, Strasbourg, France.
Improta
S
S
Cowley
D J
DJ
Guenet
C
C
Merly
J P
JP
Teufel
M
M
Saudek
V
V
D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D022061:Tacrolimus Binding Protein 1A