Narrow Results

Two challenges for G-protein coupled receptor (GPCR)-ligand docking with flexibility by computational method are: (1) how to accurately model the perturbations of the backbone when docking ligand to the receptor and (2) how to sample the backbone near the binding pocket. To address the two challenges, we propose a combined refinement (coREF) approach working on the flexibility of the docking interface by integrating two different refinement protocols based on RosettaLigand (RL) platform. The first refinement protocol generates multiple initial receptors by parallelling different movements to mimic the observed simultaneous fluctuations of backbones near the binding site without ligand conformation. The second refinement protocol adds a backbone refinement step for interface residues with ligand conformation, which extending the RL docking algorithm. To validate the performance of coREF, we refined 20 GPCR Docking 2008/2010 models submitted by participants. Eight of 10 CXCR4 targets and half of D3 targets showed lower LRMSD values than the submitted models. Nine in 12 results were slightly better than those refined using the RL docking algorithm.

Lipid mediator is the collective term for prostanoids, leukotrienes, lysophospholipids, platelet-activating factor, endocannabinoids and other bioactive lipids, that are involved in various physiological functions including inflammation, immune regulation and cellular development. They act by binding to their ligand-specific G-protein coupled receptors (GPCRs). Since 1990's a number of lipid GPCRs have been cloned in humans, with a few more identified in other vertebrates. However, the conservation of these receptors has been poorly investigated in other eukaryotes. Herein we performed a phylogenetic analysis by collecting their orthologs in 13 eukaryotes with complete genomes. The analysis shows that orthologs for prostanoid receptors are likely to be conserved in the 13 eukaryotes. In contrast, those for lysophospholipid and cannabinoid receptors appear to be conserved only in vertebrates and chordates. Receptors for leukotrienes and other bioactive lipids are limited to vertebrates. These results indicate that the lipid mediators and their receptors have coevolved with the development of highly modulated physiological functions such as immune regulation and the formation of the central nervous system. Accordingly, examining the presence and role of lipid mediator GPCR orthologs in invertebrate species can provide insight into the development of fundamental biological processes across diverse taxa.