1f40

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SOLUTION STRUCTURE OF FKBP12 COMPLEXED WITH GPI-1046, A NEUROTROPHIC LIGAND

Overview

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.

About this Structure

1F40 is a Single protein structure of sequence from Homo sapiens with GPI as ligand. Full crystallographic information is available from OCA.

Reference

Solution structure of a neurotrophic ligand bound to FKBP12 and its effects on protein dynamics., Sich C, Improta S, Cowley DJ, Guenet C, Merly JP, Teufel M, Saudek V, Eur J Biochem. 2000 Sep;267(17):5342-55. PMID:10951192

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