Mapping the Molecular Architecture Required for Lipid-Binding Pockets Using a Subset of Established and Orphan G-Protein Coupled Receptors

Shanthi Nagarajan, Zu Yuan Qian, Parthiban Marimuthu, Nabil J Alkayed, Sanjiv Kaul, Anthony P Barnes

Research output: Contribution to journalArticleScientificpeer-review

Abstract

G-protein coupled receptors (GPCRs) sense a wide variety of stimuli, including lipids, and transduce signals to the intracellular environment to exert various physiological responses. However, the structural features of GPCRs responsible for detecting and triggering responses to distinct lipid ligands have only recently begun to be revealed. 14,15-epoxyeicosatrienoic acid (14,15-EET) is one such lipid mediator that plays an essential role in the vascular system, displaying both vasodilatory and anti-inflammatory properties. We recently reported multiple low-affinity 14,15-EET-binding GPCRs, but the mechanism by which these receptors sense 14,15-EET remains unclear. Here, we have taken a combined computational and experimental approach to identify and confirm critical residues and properties within the lipid-binding pocket. Furthermore, we generated mutants to engineer selected GPCR-predicted binding sites to either confer or abolish 14,15-EET-induced signaling. Our structure-function analyses indicate that hydrophobic and positively charged residues of the receptor-binding pocket are prerequisites for recognizing lipid ligands such as 14,15-EET and possibly other eicosanoids.

Original languageEnglish
Pages (from-to)3442-3452
Number of pages11
JournalJournal of Chemical Information and Modeling
Volume61
Issue number7
DOIs
Publication statusPublished - 26 Jul 2021
MoE publication typeA1 Journal article-refereed

Keywords

  • 8,11,14-Eicosatrienoic Acid/analogs & derivatives
  • Binding Sites
  • Humans
  • Ligands
  • Lipids
  • Protein Binding
  • Receptors, G-Protein-Coupled/genetics

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