Abstract
Great progress has been made over the past decade in understanding the structural, functional, and pharmacological diversity of lipid GPCRs. From the first determination of the crystal structure of bovine rhodopsin in 2000, much progress has been made in the field of GPCR structural biology. The extraordinary progress in structural biology and pharmacology of GPCRs, coupled with rapid advances in computational approaches to study receptor dynamics and receptor-ligand interactions, has broadened our comprehension of the structural and functional facets of the receptor family members and has helped usher in a modern age of structure-based drug design and development. First, we provide a primer on lipid mediators and lipid GPCRs and their role in physiology and diseases as well as their value as drug targets. Second, we summarize the current advancements in the understanding of structural features of lipid GPCRs, such as the structural variation of their extracellular domains, diversity of their orthosteric and allosteric ligand binding sites, and molecular mechanisms of ligand binding. Third, we close by collating the emerging paradigms and opportunities in targeting lipid GPCRs, including a brief discussion on current strategies, challenges, and the future outlook.
Highlights
Lipids have attracted the attention of biochemists and cell biologists for several decades, owing to their sheer diversity and for their staggeringly broad cellular and physiological roles
The G protein-coupled receptors (GPCRs) are transmembrane proteins that reside on cell surfaces and govern a plethora of cellular communications and signaling processes
As many as 50 different GPCRs are estimated to be liganded by lipid mediators, of which 36 unique receptors belong to class A GPCRs [19]
Summary
Lipids have attracted the attention of biochemists and cell biologists for several decades, owing to their sheer diversity and for their staggeringly broad cellular and physiological roles These largely hydrophobic, bioactive molecules modulate a variety of structural and functional aspects central to life, ranging from constituting cellular and organellar membranes, energy storage, protein post-translational modifications, and cell signaling. Pharmaceuticals 2022, 15, 12 lipid mediators, some representative examples of which are illustrated, and their repertoire is continually expanding. Bioactive lipid mediators can be categorized in three broad classes—(1) arachidonic (AA)-derivedeicosanoids; eicosanoids;(2)(2)lysophospholipids lysophospholipids and their derivatives (including acid (AA)-derived and their derivatives (including enendocannabinoids); and omega-3-derivedspecialized specializedpro-resolving pro-resolvingmediators mediators(SPMs) Another important group of lipid mediators comprises fatty acids with medium to long acyl chains. Malfunctional signaling pathways found atcenter the cennumerous human disorders [3], extensively summarized in
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