1F40

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

Summary for 1F40

• Entry DOI: 10.2210/pdb1f40/pdb
• Related: 1fkg 1fkj
• Descriptor: FK506 BINDING PROTEIN (FKBP12), (2S)-[3-PYRIDYL-1-PROPYL]-1-[3,3-DIMETHYL-1,2-DIOXOPENTYL]-2-PYRROLIDINECARBOXYLATE (2 entities in total)
• Functional Keywords: isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 12196.95

Authors

Sich, C.,Improta, S.,Cowley, D.J.,Guenet, C.,Merly, J.P.,Teufel, M.,Saudek, V. (deposition date: 2000-06-07, release date: 2000-11-08, Last modification date: 2024-05-22)

Primary citation

Sich, C.,Improta, S.,Cowley, D.J.,Guenet, C.,Merly, J.P.,Teufel, M.,Saudek, V.
Solution structure of a neurotrophic ligand bound to FKBP12 and its effects on protein dynamics.
Eur.J.Biochem., 267:5342-5354, 2000

PubMed 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.

PubMed: 10951192
DOI: 10.1046/j.1432-1327.2000.01551.x

Experimental method

SOLUTION NMR