Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174

Abstract

Lysophosphatidylserine (LysoPS) is a naturally occurring lipid mediator involved in various physiological and pathological processes especially those related to the immune system. GPR34, GPR174, and P2Y10 have been identified as the receptors for LysoPS, and its analogues have been developed as agonists or antagonists for these receptors. However, the lack of structural information hinders the drug development with novel characteristics, such as nonlipid ligands and allosteric modulators. Here, we determined the structures of human GPR34 and GPR174 in complex with LysoPS and G protein by cryo-EM. Combined with structural analysis and functional studies, we elucidated the lipid-binding modes of these receptors. By structural comparison, we identified the structural features of GPR34 and GPR174 in active state. Taken together, our findings provide insights into ligand recognition and signaling of LysoPS receptors and will facilitate the development of novel therapeutics for related inflammatory diseases and autoimmune diseases.

Molecular insights into the atypical activation mechanism of GPR156 in maintaining auditory function

“…The samples of GPR156 were prepared in three independent replicates. Additionally, two well-established class A GPCRs (including GPR34 ( 50, 51 ) and GPR174 ( 51–53 )), each with two replicates, were employed as control groups where no phospholipids with two chains were present. A Dionex U3000 UHPLC (Waters Corporation, Milford, USA) fitted with Q-Exactive mass spectrometer equipped with heated electrospray ionization (ESI) source (Thermo Fisher Scientific, Waltham, MA, USA) was used to analyze the metabolic profiling in both ESI positive and ESI negative ion modes.…”

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

“…Using synthetic structural analogs of lyso-PS coupled with homology modeling and molecular dynamics studies, the first study shows how GPR34 orients itself within the membrane bilayer to bind lyso-PS and subsequently activate intracellular pathways . Very recently, a few reports describe the three-dimensional structure of human GPR34 in complex with Gα i and lyso-PS (or its structural analogs) solved by cryoelectron microscopy. − Further, these structural studies extensively characterize the ligand binding pocket of human GPR34 and, together with molecular dynamics simulations, mutagenesis, and modeling, provide an explanation for the lyso-PS ligand specificity for this GPCR. − …”

“…Yet, to the best of our knowledge, no such small molecule modulators (antagonists) to GPR174 have been reported. However, very recently, a few reports describe the three-dimensional structures of human GPR174 bound to lyso-PS in complex with the Gα s G-protein that were solved using cryoelectron microscopy. ,, These structures of the ternary complex provide new insights into the selective ligand (lyso-PS) recognition by GPR174 and activation of this receptor upon lyso-PS binding and coupling to the Gα s G-protein ,, and should now pave the way for developing antagonists to GPR174.…”