Lipoxygenase 2 from Cyanothece sp. controls dioxygen insertion by steric shielding and substrate fixation

We have recently completed a full re-architecturing of the ROSETTA molecular modeling program, generalizing and expanding its existing functionality. The new architecture enables the rapid prototyping of novel protocols by providing easy-to-use interfaces to powerful tools for molecular modeling. The source code of this rearchitecturing has been released as ROSETTA3 and is freely available for academic use. At the time of its release, it contained 470,000 lines of code. Counting currently unpublished protocols at the time of this writing, the source includes 1,285,000 lines. Its rapid growth is a testament to its ease of use. This chapter describes the requirements for our new architecture, justifies the design decisions, sketches out central classes, and highlights a few of the common tasks that the new software can perform. © 2011 Elsevier Inc. All rights reserved.

Prostaglandins, leukotrienes, platelet-activating factor, lysophosphatidic acid, sphingosine 1-phosphate, and endocannabinoids, collectively referred to as lipid mediators, play pivotal roles in immune regulation and self-defense, and in the maintenance of homeostasis in living systems. They are produced by multistep enzymatic pathways, which are initiated by the de-esterification of membrane phospholipids by phospholipase A2s or sphingo-myelinase. Lipid mediators exert their biological effects by binding to cognate receptors, which are members of the G protein-coupled receptor superfamily. The synthesis of the lipid mediators and subsequent induction of receptor activity is tightly regulated under normal physiological conditions, and enzyme and/or receptor dysfunction can lead to a variety of disease conditions. Thus, the manipulation of lipid mediator signaling, through either enzyme inhibitors or receptor antagonists and agonists, has great potential as a therapeutic approach to disease. In this review, I summarize our current state of knowledge of the synthesis of lipid mediators and the function of their cognate receptors, and discuss the effects of genetic or pharmacological ablation of enzyme or receptor function on various pathophysiological processes.