Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate

Abstract

Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR–G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P1) and heterotrimeric Gi complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA1) and Gi complexes in the presence of LPA. Our structural and functional data provide insights into how LPA and S1P adopt different conformations to interact with their cognate GPCRs, the selectivity of the homologous lipid GPCRs for S1P versus LPA, and the different activation mechanisms of these GPCRs by LPA and S1P. Our studies also reveal specific optimization strategies to improve the MS-treating S1P1-targeting drugs.

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

“…61 A data processing 'decoy' refinement strategy was implemented at this step to improve map resolution as described previously. 66 Micrographs were over-picked with particles using a Laplacian of Gaussian filter in Relion 3.0. 61 Particles were subjected to a round of reference-free 2D classification in cryoSPARC3.0 to remove ice contaminants.…”

A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB2 Receptor via the Lipid Bilayer

“…Of note is the conformation of Phe283 7.37 , which in the gauche+ conformation, like that observed in the crystal structures of CB 2 R, ,, closes the tunnel, whereas in the trans conformation, it opens it. Moreover, it has been shown that the N-terminus of the S1P 1 receptor packs against ECL-2 in the active conformation, leading to an opening of the ligand access vestibule between TMs 1 and 7 . Thus, we have quantified in Figure S3 the number of snapshots, during the 100 μs of MD simulation, in which Phe283 7.37 adopts the trans conformation or/and the distance between the top of TMs 1 (Cα atom of Thr34 1.33 ) and 7 (Cα atom of Val277 7.31 ) increases from the initial value of 14.5 Å to values larger than 15.5 Å. GPCRs are dynamic proteins that permit rapid small-scale structural fluctuations, and accordingly, both events can be freely observed, simultaneously or not, during the calculated trajectories (Figure S3).…”

Design, Synthesis and Biological Evaluation of Potent and Selective S1PR1 Agonists for the Treatment of Ulcerative Colitis

“…To rapidly construct effective S1PR1 agonists, we analyzed the binding mode of the representative compound BAF312 in detail. Three BAF312‐bound S1PR1 complex structures resolved by cryo‐EM have been disclosed (PDB ID: 7TD4, [ 25 ] 7EVY, [ 26 ] 7EO4, [ 27 ] Figure 2A). BAF312 exhibits the following conformational features: Hydrophobic tails consisting of benzene and cyclohexyl groups extend into the hydrophobic pockets with the trifluoromethyl substrates orienting towards the gap between TM5 and TM6 (Figure 3).…”

“…The molecular docking tool Glide module (maestro version 11.5) was used to dock BAF312 and compounds 9a — 9k to three BAF312 bound S1PR1 cryo‐EM structures (accession code in the Protein Data Bank: 7EVY, [ 26 ] 7EO4 [ 27 ] and 7TD4 [ 25 ] ).…”