The Protein-G Coupled Recetors : Study of the leucotrien receptors

In collaboration with Jean-Louis Banères's team in the faculty of pharmacy in Montpellier (Institut des Biomolécules Max Mousseron, UMR5247) and the high field NMR team of the ICSN (UPR2301, Gif/Yvette) we study the fixation dynamics of ligands on the two receptors, BLT1 and BLT2, to the B4 leucotrien (LTB4), belonging to the group of receptors called "chemoattractant".

The leucotriens have been discovered about thirty years ago by studying the proinflammatory derivatives of arachidonic acid in the leucocytes. In vivo, these receptors particularly block the recruitment of leucocytes (neutrophiles) to the inflammatory sites. BLT1 is highly selective to the LTB4 whereas BLT2 has a lower affinity and is less specific to the LTB4.

The classical approach by X-ray Crystallography is long, does not give information on the dynamics of the binding process, and cannot be used to study various molecules of pharmacological interest. Our purpose is to determine the structure of the ligand bound to their receptors by NMR. We have developed a novel and fast approach, requiring very little quantity of receptor (20 microM), that associates NMR with a new method of renaturation of membrane proteins in the presence of surfactants developed in the laboratory, the amphipols.

These structural data on ligands bound to their receptors will give us, on one hand, precious information of the protein/ligands interactions and will, on the other hand, lead us to the development of more effective molecules in a therapeutical purpose.

Revue in the domain : Izumi et al. (2002) J. Biochem., 132, 1-6