Structural and conformational studies of biased agonism through formyl peptide receptors.

Abstract

G protein-coupled chemoattractant receptors are class A GPCRs that couple primarily to the Gi class of heterotrimeric G proteins. Initially identified for their abilities to mediate leukocyte chemotaxis, chemoattractant GPCRs such as the formyl peptide receptors (FPRs) have been known for their diverse cellular functions in response to a variety of agonists. Stimulation of FPR2, in particular, leads to ligand-dependent activation of proinflammatory signaling as well as anti-inflammatory and proresolving signaling. Recently, the structures of FPR2-Gi protein complexed with ligands of different compositions have been solved by crystallization and cryo-electron microscopy. Analysis of the structural data as well as molecular simulation has led to the findings that the FPR2 binding pocket is sufficiently large for accommodation of several different types of ligands but in different poses. This mini-review focuses on the structural and conformational aspects of FPR2 for mechanisms underlying its biased agonism.