1F40

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

1F40 の概要

• エントリーDOI: 10.2210/pdb1f40/pdb
• 関連するPDBエントリー: 1fkg 1fkj
• 分子名称: FK506 BINDING PROTEIN (FKBP12), (2S)-[3-PYRIDYL-1-PROPYL]-1-[3,3-DIMETHYL-1,2-DIOXOPENTYL]-2-PYRROLIDINECARBOXYLATE (2 entities in total)
• 機能のキーワード: isomerase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12196.95

構造登録者

Sich, C.,Improta, S.,Cowley, D.J.,Guenet, C.,Merly, J.P.,Teufel, M.,Saudek, V. (登録日: 2000-06-07, 公開日: 2000-11-08, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

SOLUTION NMR