Structure of the agonist 12–HHT in its BLT2 receptor-bound state

Abstract

G Protein-Coupled receptors represent the main communicating pathway for signals from the outside to the inside of most of eukaryotic cells. They define the largest family of integral membrane receptors at the surface of the cells and constitute the main target of the current drugs on the market. The low affinity leukotriene receptor BLT2 is a receptor involved in pro-and anti-inflammatory pathways and can be activated by various unsaturated fatty acid compounds. We present here the NMR structure of the agonist 12-HHT in its BLT2-bound state and a model of interaction of the ligand with the receptor based on a conformational homology modeling associated with docking simulations. Put into perspective with the data obtained with leukotriene B4, our results illuminate the ligand selectivity of BLT2 and may help define new molecules to modulate the activity of this receptor.

Discovery of Irbesartan Derivatives as BLT2 Agonists by Virtual Screening

“…The top rated superposition was examined manually and subsequently refined using the Flexible Alignment routine. A previous publication on the conformation of 12-( S )-HHT in the receptor bound state by Giusti et al demonstrated the importance of the interactions of the carboxylic group and the −OH group which is supposed to act as a H-bond acceptor . These observations were in perfect agreement with the SAR of CAY10583, where the removal of the acidic or the H-bond acceptor group resulted in fully inactive derivatives.…”

“…A previous publication on the conformation of 12-(S)-HHT in the receptor bound state by Giusti et al demonstrated the importance of the interactions of the carboxylic group and the −OH group which is supposed to act as a H-bond acceptor. 13 These observations were in perfect agreement with the SAR of CAY10583, where the removal of the acidic or the H-bond acceptor group resulted in fully inactive derivatives. Therefore, we used default settings for refinement of the existing alignment, while weights for H-Bond acceptor and carboxylate (O 2 )-type Centroid were set to 10.…”

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

“…This was facilitated by the isolation of receptor in partially deuterated amphipols [ 230 ]. Recently, ligand selectivity was examined by comparing the binding of LTB4 and agonist 12-HHT to the same receptor in perdeuterated amphipols [ 231 ]. While structural information on various 7TM receptors, such as bacteriorhodopsin and melanocortin-2 and -4, has been reported in solution [ 232 , 233 ], it is not known whether these investigations using amphipols have progressed beyond a proof of principle.…”